bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–07–12
57 papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Metabolic reprogramming of macrophages during mycobacterial infection: a review of immunometabolic crosstalk and pathogen manipulation.
  2. AMPK-driven immunometabolic reprogramming enhances CD19+CD21hiCD24hi regulatory B cell-mediated suppression of atopic dermatitis.
  3. Metabolic regulation of macrophage polarization in myocardial infarction: from mechanisms to targeted therapies.
  4. Engineering T cell metabolism to enhance therapeutic efficacy.
  5. Comparative lipidomic and transcriptomic profiling reveals distinct fatty acid utilization in T and B cells across mouse and human.
  6. Provision of preferred nutrients to macrophages promotes Salmonella intracellular replication without relying on Type III secretion systems.
  7. Dopamine signaling reprograms macrophage FAO to alleviate acute lung injury by inhibiting NETosis via the CXCL10-CXCR3 axis.
  8. Immunometabolic reprogramming and mitochondrial dysfunction in acute respiratory distress syndrome: mechanisms, metabolic resilience, and therapeutic perspectives- a narrative review.
  9. Reprogramming macrophage immunometabolism via glutamine antagonism potentiates colorectal cancer therapy in mice.
  10. Myeloid MMP14 couples extracellular proteolysis to inflammatory and metabolic remodeling during obesity.
  11. Reprogramming macrophage metabolism for cardiovascular therapy: From molecular pathways to precision nanomedicine.
  12. SIRT5-dependent regulation of ASL controls arginine metabolism and T cell function.
  13. Metabolic determinants of autoimmune kidney diseases.
  14. Gut-derived cinnamic acid limits allergic airway inflammation via the SAT1-spermidine-eIF5A hypusination axis.
  15. Cholinergic regulation of neuroinflammation: linking microglia, immunometabolism, and neuromodulation.
  16. CSF1R regulates monocyte subset differentiation and intracellular metabolism.
  17. Dioscin suppresses colitis-associated colorectal tumorigenesis by inhibiting PPARγ-mediated fatty acid oxidation in TAMs.
  18. Adenosine as a metabolic checkpoint in CD8+ T cell dysfunction.
  19. Restoring immune homeostasis in the spinal microenvironment: targeting mechano-inflammation and immunometabolic reprogramming.
  20. Type 2 Inflammatory Diseases: The Crossroads of Immunity and Metabolism.
  21. Dysfunctional Mitochondria in Microglia Drive Cognitive Aging and Neurodegeneration via cGAS-STING.
  22. Adipocyte OX40L promotes adipose T cell activation and insulin resistance in obesity.
  23. CHAC2-mediated glutathione metabolic reprogramming drives N1 polarization of bone marrow neutrophils and exacerbates inflammatory comorbidities.
  24. Phenylalanine exacerbates psoriasiform inflammation through NF‑κB‑mediated dendritic cell activation and Th17 polarization.
  25. USP18-driven macrophage M2 polarization through fatty acid β-oxidation inhibits immune responses induced by RSV infection.
  26. Tangeretin ameliorates sepsis-induced neurocognitive impairment in adult male mice by suppressing Akt-driven glycolytic reprogramming and neuroinflammation.
  27. Dipeptidyl peptidase 3 sets the threshold for immune activation and survival during experimental bacterial infection.
  28. Immunometabolic Reprogramming of Fibroblastic Reticular Cells in the Tumor Immune Microenvironment.
  29. Hemocyanin is associated with GAPDH-related glycolytic metabolism during anti-Vibrio responses in Penaeus vannamei.
  30. Latent Cerebral Toxoplasma Gondii Infection Induces the Kynurenine Pathway and Production of Neurotoxic Metabolites.
  31. Glycolysis‑driven immunosuppression in gastric cancer: Metabolic crosstalk between tumor cells and the immune microenvironment (Review).
  32. Mitochondrial STAT3-mediated suppression of apoptosis constrains antimycobacterial immunity.
  33. Disrupting the adiposopathy-inflammation loop: a translational immunometabolic framework for inflammatory disease.
  34. An acidic welcome: How microbial metabolites keep fungi in line.
  35. Crosstalk Between Immunometabolic Pathways in Non-Small Cell Lung Cancer.
  36. Depletion of extracellular asparagine impairs self-reactive T cells and ameliorates autoimmunity in a murine model of multiple sclerosis.
  37. Gut Microbiota, Immunity, and Metabolism in the Progression From Chronic Liver Disease to Hepatocellular Carcinoma.
  38. Staphylococcus aureus rewires arginine metabolism to drive mammary aging via macrophage-epithelial crosstalk.
  39. Aging reprograms the functional, epigenetic, and metabolic landscape of macrophages.
  40. Jack-of-a-new-trade: Itaconate targets the PPP/G6PD to control lung cancer.
  41. A metabolic amplification strategy for spherical nucleic acid immunogenicity driven by simvastatin-CpG codelivery.
  42. Tricarboxylic Acid (TCA) Cycle Enzyme Alpha-Ketoglutarate Dehydrogenase (KGDH) as a Nexus for the Regulation of Macrophage Polarization.
  43. Novel duck reovirus σC hijacks the mitochondrial COQ6-CoQ10 axis to drive NLRP3-dependent pyroptosis.
  44. Hijacking Sodium-Glucose Cotransporters: Fructose Drives Neuronal and Microglial Dysfunction.
  45. Liquiritigenin ameliorates adipocyte insulin resistance by inhibiting pro-inflammatory polarization of macrophages via regulation of the mtROS/OXPHOS axis.
  46. Immune protection and persistence in Pseudomonas aeruginosa infections by pyruvate cross-feeding.
  47. An IGF2BP3-dependent metabolic circuit governs macrophage recruitment and immunosuppression in glioblastoma.
  48. Metabolic and epigenetic regulation of microglia memory in neurological disorders.
  49. The lactylation axis: bridging metabolic reprogramming and immunosuppression in the tumor microenvironment.
  50. Intestinal lipid metabolism controls immune response through NHR-68 and gut-brain signaling in C. elegans.
  51. Japanese encephalitis virus hijacks the host purine biosynthetic network to promote viral replication in neurons.
  52. ETV4 enhances glycolysis to suppress NK-cell cytotoxicity in the immune microenvironment of colon cancer.
  53. Sex specific pattern of adipose expansion, inflammation and dysfunction with short term high fat diet exposure.
  54. Mucin degradation by Akkermansia muciniphila promotes Alistipes-dependent tryptophan metabolism and Th17-driven autoimmunity.
  55. Sp1 links CD46 to CD4 T cell metabolic fitness, survival, and retroviral control.
  56. Metabolic regulation and immunosuppressive functions of lipid-associated macrophages in pancreatic ductal adenocarcinoma.
  57. Macrophage-mediated nutrient recycling: evolutionary insights into the metabolic role of professional phagocytes.
  1. Front Cell Infect Microbiol. 2026 ;16 1806805
    Metabolic reprogramming of macrophages during mycobacterial infection: a review of immunometabolic crosstalk and pathogen manipulation.
    Xiaohe Lu, Yanping Zhao, Pingfan Qin, Yongquan Shi, Xiong Xiao.
      Macrophages undergo dynamic metabolic reprogramming that critically shapes their functional polarization and antimicrobial responses during mycobacterial infection. This review integrates current knowledge on how infection reprograms major metabolic pathways in macrophages. Mycobacterial infection triggers a complex and often dual-purposed rewiring of glycolysis, the tricarboxylic acid (TCA) cycle, and amino acid metabolism. Pathogens actively manipulate these pathways to simultaneously suppress host antimicrobial effector functions and acquire nutrients for their own survival. Enhanced glycolysis, typically linked to M1 macrophages, can be exploited by the pathogen. Reprogramming of the TCA cycle, particularly through metabolites like itaconate, drives macrophages polarization toward an M2 phenotype that favors bacterial persistence. Amino acid metabolism becomes a site of metabolic competition where the bacterium secures substrates such as arginine and tryptophan to induce M2 phenotype, while the host attempts to sustain M1 macrophage functions through glutamine metabolism and the arginine nitric oxide pathway. Fatty acid metabolism further contributes to macrophage polarization in a context dependent manner. Understanding this immunometabolic interplay provides novel insights into tuberculosis pathogenesis and highlights metabolic pathways as potential targets for host-directed therapies. Future research should clarify the heterogeneity of metabolic responses across different mycobacterial species, infection stages, and macrophage subsets to guide therapeutic strategies.
    Keywords:  TCA cycle; amino acid metabolism; fatty acid metabolism; glycolysis; immunometabolic interplay; macrophages; mycobacterial infection
    DOI:  https://doi.org/10.3389/fcimb.2026.1806805
  2. J Allergy Clin Immunol. 2026 Jul 07. pii: S0091-6749(26)00480-X. [Epub ahead of print]
    AMPK-driven immunometabolic reprogramming enhances CD19+CD21hiCD24hi regulatory B cell-mediated suppression of atopic dermatitis.
    Seung Taek Lee, Ha Eun Kim, So-Yeon Kim, Jong Yeong Lee, Kyung-Hwa Nam, Sang-Hyun Kim, Jun-Young Park, Jin Kyeong Choi.
       BACKGROUND: Atopic dermatitis (AD) is characterized by dysregulated immune responses and persistent inflammation. Regulatory B cells (Bregs) suppress inflammation, but the metabolic mechanisms constraining their function in AD remain unclear.
    OBJECTIVE: We sought to define whether immunometabolic regulation governs Breg differentiation and function in AD.
    METHODS: Mouse and human B cells were stimulated with the AMPK activator AICAR under inflammatory conditions, with genetic and pharmacologic perturbations. Functional and mechanistic analyses were performed using co-culture systems, a 2,4-dinitrochlorobenzene (DNCB) and Dermatophagoides farinae extract (DFE)-induced murine model of AD, adoptive transfer approaches, adoptive transfer, and human PBMCs from patients with AD.
    RESULTS: AICAR treatment or adoptive transfer of AICAR-induced Bregs significantly attenuated AD-like inflammation, whereas AMPK inhibition or IL-10 blockade abrogated these effects. Mechanistically, AICAR induced IL-10-producing Bregs through AMPK-dependent suppression of mTOR signaling and mitochondrial reactive oxygen species while preserving oxidative phosphorylation. This reprogramming selectively enhanced regulatory B cell function and suppressed STAT1 signaling without affecting STAT3. Functionally, these Bregs suppressed Th1, Th2, and Th17 responses in an IL-10-dependent manner without expanding Foxp3+ regulatory T cells. In human PBMCs from patients with AD, AICAR restored immunometabolic coupling by increasing IL-10-producing B cells and reducing pro-inflammatory cytokine production.
    CONCLUSION: These findings identify an AMPK-mTOR-redox metabolic checkpoint that governs regulatory B cell function and restrains AD inflammation, linking metabolic control to immune regulation.
    Keywords:  AMPK; Atopic dermatitis; B cell regulation; IL-10; Immunometabolism; Inflammation; Metabolic reprogramming; Mitochondrial reactive oxygen species; Regulatory B cells; mTOR
    DOI:  https://doi.org/10.1016/j.jaci.2026.06.015
  3. J Transl Med. 2026 Jul 07.
    Metabolic regulation of macrophage polarization in myocardial infarction: from mechanisms to targeted therapies.
    Lihuimei Zhou, Yi Jiang, Jing Luo, Jiafu Li.
       BACKGROUND: Myocardial infarction (MI) elicits a tightly staged immune response in which macrophages coordinate early inflammation, subsequent tissue repair, and long-term ventricular remodeling. Growing evidence indicates that macrophage polarization is directed by immunometabolic reprogramming; however, the metabolic circuits that connect immune function to durable cardiac recovery remain incompletely defined.
    CONTENT: This review integrates current insights into the spatiotemporal, metabolic, and functional regulation of macrophages after MI. We summarize how glucose metabolism (glycolysis and the pentose phosphate pathway), TCA cycle rewiring and immunometabolic intermediates, lipid and amino-acid metabolism, iron handling and ferroptosis, purinergic and NAD⁺-dependent signaling, oxidative stress pathways, and vitamin-dependent regulation shape inflammatory versus reparative macrophage states. We highlight drug-targetable mediators-including lactate, succinate, α-KG, itaconate, kynurenine, and NAD⁺-linked pathways-and discuss how stage-specific targeting may suppress early injurious inflammation while promoting reparative remodeling. We also review advances in nanotechnology- and exosome-based delivery platforms that enable cardiac macrophage-directed interventions.
    OUTLOOK: Clinical translation will require deeper characterization of human macrophage heterogeneity, development of in vivo metabolic biomarkers, and validation in prospective multi-omics-anchored human studies. Temporally controlled combination therapies coupled with precision delivery systems may maximize cardiac repair while minimizing systemic metabolic toxicity.
    CONCLUSIONS: Macrophage immunometabolism is a central determinant of post-MI healing and remodeling. Therapeutic reprogramming of macrophage metabolism represents a promising precision-immunotherapy strategy to improve repair, limit heart failure progression, and expand future cardiovascular treatment options.
    CLINICAL TRIAL NUMBER: Not applicable.
    Keywords:  Immunology; Inflammation; Macrophage polarization; Metabolic regulation; Myocardial infarction
    DOI:  https://doi.org/10.1186/s12967-026-08472-9
  4. Adv Pharmacol. 2026 ;pii: S1054-3589(26)00030-X. [Epub ahead of print]106 117-139
    Engineering T cell metabolism to enhance therapeutic efficacy.
    Laura Anderson, Nicola J Mason, Roddy S O'Connor.
      Adoptive cell therapies, particularly chimeric antigen receptor (CAR) T cells, function as "living drugs" whose efficacy depends not only on target recognition but also on the metabolic state of the infused product. T cell metabolism governs energy production, redox homeostasis, biomass generation, and adaptation to persistent antigen exposure and nutrient stress, thereby shaping expansion, effector function, persistence, and susceptibility to exhaustion. Core metabolic programs relevant to these outcomes include glycolysis and mitochondrial respiration, anaplerosis and amino acid metabolism, lipid metabolism, and NAD- and redox-linked pathways. These programs help determine adoptive cell therapy-relevant phenotypes, including the balance between immediate cytotoxicity and long-term durability. Increasing evidence further suggests that metabolism can be therapeutically manipulated across the lifecycle of adoptive cell therapy through ex vivo manufacturing, receptor and signaling design, direct gene engineering, and post-infusion support. Collectively, these findings support a pharmacologic framework in which metabolic state is not merely a descriptive correlate of product quality, but a controllable determinant of therapeutic performance. A deeper mechanistic understanding of these pathways may enable more precise strategies to improve persistence, function, and long-term antitumor efficacy.
    Keywords:  Adoptive cell therapy; CAR T cells; Ex vivo manufacturing; Metabolic engineering; Metabolic programming; Mitochondrial fitness; T cell exhaustion; T cell metabolism; T cell persistence; Tumor microenvironment
    DOI:  https://doi.org/10.1016/bs.apha.2026.05.001
  5. Sci Rep. 2026 Jul 06.
    Comparative lipidomic and transcriptomic profiling reveals distinct fatty acid utilization in T and B cells across mouse and human.
    Keiko Nakano, Kiyoe Sumi, Keisuke Miyako, Arisa Ito, Toshiyuki Kobayashi, Keisuke Yamamoto, Yukie Iwao, Toshio Kanno, Takaharu Kimura, Satoru Yokoyama, Kazuko Yamada, Hikari K Asou, Mayumi Maruyama, Yoko Suzuki, Yusuke Kawashima, Osamu Ohara, Yusuke Endo.
      Lipid metabolism is increasingly recognized as a critical determinant of immune cell differentiation and function, yet the metabolic programs that distinguish closely related adaptive immune cell subsets remain incompletely defined. Here we demonstrate that T and B cells employ distinct fatty acid utilization strategies across species. Integrated lipidomic and transcriptomic analyses of mouse and human lymphocytes revealed enrichment of long-chain phospholipid species in T cells, including prominent increases in arachidonic acid-containing lipids, accompanied by elevated expression of fatty acid elongation-associated genes including Elovl5. In contrast, B cells preferentially accumulated phospholipids with shorter and/or more unsaturated acyl chains, notably with consistent enrichment of eicosapentaenoic acid-containing lipids, together with increased expression of genes involved in fatty acid uptake, desaturation, and phospholipid remodeling, including Cd36, Scd1, and Lpgat1. Acyl-chain pairing analyses further uncovered distinct organizational patterns in lipid assembly, and cross-species comparisons revealed both conserved features and marked species-specific divergence, highlighting shared metabolic principles in mouse and human lymphocytes. Our data indicate that differential fatty acid elongation, uptake, and remodeling programs shape lineage-specific lipid architectures and contribute to metabolic specialization in adaptive immune cells.
    Keywords:  B cells; Fatty acid metabolism; Immunometabolism; Lipidomics; Membrane composition; T cells
    DOI:  https://doi.org/10.1038/s41598-026-61151-z
  6. PLoS Pathog. 2026 Jul;22(7): e1014348
    Provision of preferred nutrients to macrophages promotes Salmonella intracellular replication without relying on Type III secretion systems.
    Francisco-Javier Garcia-Rodriguez, Paula Martinez-Oca, Camila Valenzuela, Joaquin Bernal-Bayard, Pedro Escoll.
      Intracellular survival and replication within macrophages are key virulence determinants of Salmonella enterica serovar Typhimurium. This phenomenon is traditionally attributed to the activity of its two Type III Secretion Systems (T3SS) and their associated effectors. A critical challenge for these bacteria is acquiring nutrients from inside the host cell. Thus, they modulate the metabolism of host cells to replicate. Given the metabolic plasticity of macrophages, a key unresolved question is how their metabolic heterogeneity shapes intracellular Salmonella replication. By using human primary macrophages and live-cell imaging to monitor bacterial dynamics at the single-cell level, we revealed that Salmonella does not replicate in all infected cells. However, supplementation with specific carbon sources used by Salmonella during infection accelerated bacterial replication and increased the proportion of macrophages harboring replicative bacteria. Remarkably, this occurred even in the absence of functional T3SSs, as a ΔprgH/ΔssaV double mutant was able to replicate in a subset of infected cells under favorable nutrient conditions. These phenotypes are further amplified in macrophages with higher glycolytic activity, such as the murine RAW 264.7 cell line. Further analyses demonstrated that enhanced Salmonella replication is not strictly dependent on host glycolytic activity but is instead driven by the ability of the host cell to take up the nutrients Salmonella prefers for its replication early during infection. In summary, our findings suggest that the dependence of Salmonella on its T3SSs for intracellular replication can be compensated, at least partially, when host cells provide optimal access to key nutrients. This underscores the role of host cell metabolism in shaping intracellular bacterial replication and highlights the crucial functions of T3SS effectors in remodelling macrophage metabolism and endosomal trafficking to establish nutrient-permissive niches. When equivalent metabolic conditions are achieved by other means in vitro, dependence on T3SSs for intracellular replication can be partially compensated in macrophages.
    DOI:  https://doi.org/10.1371/journal.ppat.1014348
  7. Mol Med. 2026 Jul 04.
    Dopamine signaling reprograms macrophage FAO to alleviate acute lung injury by inhibiting NETosis via the CXCL10-CXCR3 axis.
    Ximing Liao, Changwen Deng, Jing Gao, Ziqi Yang, Tian Li, Jialin Yao, Muyun Wang, Fengyang Xie, Zhaoqi Li, Kun Wang, Qiang Li, Di Wu, Wujian Xu, Wei Gao.
       BACKGROUND: Dysregulated innate immunity and oxidative stress drive the pathogenesis of acute lung injury/acute respiratory distress syndrome (ALI/ARDS), yet master endogenous regulators that orchestrate inflammation resolution remain elusive.
    METHODS: This study employed public database mining, clinical data investigation, murine disease models, mouse bone marrow-derived macrophages and neutrophils, and human macrophages from healthy donors and ARDS patients, to investigate the dynamic changes of the dopaminergic signaling system in the acute pulmonary inflammatory environment and its role in regulating macrophage metabolism and neutrophil extracellular trap formation (NETosis).
    RESULTS: Public database mining and experimental data reveal accelerated dopamine (DA) turnover during ALI. DA, signaling via D1-like receptors, reprograms macrophage metabolism by enhancing carnitine palmitoyltransferase 1 A (CPT1A)-dependent fatty acid oxidation (FAO) and mitochondrial fitness, which is coupled with the suppression of MAPK/NF-κB and NLRP3 inflammasome activation. These modulated macrophages restrain neutrophilic inflammation by secreting IL-10 to inhibit the CXCL10-CXCR3 axis, thereby curtailing neutrophil hyperactivation and pathogenic NETosis. Crucially, this protective mechanism is conserved in human macrophages from both healthy donors and ARDS patients.
    CONCLUSION: Our findings establish DA as a therapeutic target for recalibrating innate immunity in ALI, providing a mechanistically grounded framework for targeting dopaminergic signaling to resolve dysregulated inflammation, with exploratory preclinical translational implications for ALI/ARDS therapy.
    Keywords:  Acute lung injury; Dopamine; Macrophage metabolism; Mitochondrial homeostasis; Neutrophil extracellular traps
    DOI:  https://doi.org/10.1186/s10020-026-01549-7
  8. J Transl Med. 2026 Jul 10.
    Immunometabolic reprogramming and mitochondrial dysfunction in acute respiratory distress syndrome: mechanisms, metabolic resilience, and therapeutic perspectives- a narrative review.
    Thejesh Srinivas, Gagana Hanumaiah, Danavath Nagendra, Shwethapriya R, Souvik Chaudhuri, Vinutha R Bhat, Shobha U Kamath.
       BACKGROUND: Acute respiratory distress syndrome (ARDS) is a biologically heterogeneous condition in which patients exposed to similar injurious stimuli often develop markedly different clinical trajectories and outcomes. While inflammation is central to ARDS pathogenesis, inflammatory burden alone does not fully explain the variability in disease progression, treatment response, or recovery. Emerging evidence suggests that immunometabolic reprogramming, characterized by increased glycolysis, impaired mitochondrial oxidative phosphorylation, and altered metabolite signalling, plays a critical role in shaping immune-cell activation, inflammatory persistence, and tissue repair during critical illness.
    MAIN BODY: This narrative review synthesizes current evidence linking immunometabolic reprogramming and mitochondrial dysfunction to the clinical heterogeneity observed in ARDS. During acute lung injury, immune and structural lung cells undergo metabolic shifts characterized by increased glycolysis, impaired mitochondrial oxidative phosphorylation, and accumulation of bioactive metabolites such as lactate, succinate, and extracellular adenosine triphosphate (ATP). Beyond reflecting metabolic stress, these metabolites function as signalling mediators that are associated with amplified inflammatory pathways, compromised alveolar-capillary barrier integrity, and sustained lung injury. Multi-omic studies further demonstrate that distinct metabolic signatures are associated with ARDS phenotypes, disease severity, and treatment responsiveness. We integrate these findings within the concept of metabolic resilience, defined as the host's capacity to restore coordinated mitochondrial function, redox balance, and substrate utilization following inflammatory stress. Therapeutic strategies aimed at preserving mitochondrial function, restoring nicotinamide adenine dinucleotide (NAD⁺) homeostasis, and modulating maladaptive immunometabolic signalling may offer new avenues for precision-based interventions in ARDS.
    CONCLUSIONS: Immunometabolic reprogramming and mitochondrial dysfunction represent central biological axes linking cellular bioenergetics with clinical heterogeneity in ARDS. Understanding metabolic resilience may help refine phenotyping strategies and support development of metabolism-targeted therapies aimed at improving outcomes in this complex syndrome.
    CLINICAL TRIAL NUMBER: Not applicable.
    Keywords:  Acute respiratory distress syndrome (ARDS); Clinical trajectories; Immunometabolism; Metabolic resilience; Mitochondrial dysfunction
    DOI:  https://doi.org/10.1186/s12967-026-08585-1
  9. Nat Commun. 2026 Jul 04.
    Reprogramming macrophage immunometabolism via glutamine antagonism potentiates colorectal cancer therapy in mice.
    Renming Fan, Xintong Lu, Bingjie Zhang, Zhuang Hou, Ting Zhao, Yongrui Hai, Ye Chen, Wenhui Wang, Yue Chen, Qiu Sun, Lei Liang, Le Yang, Gaofei Wei.
      Colorectal cancer (CRC) often exhibits a suppressive tumor microenvironment that is associated with elevated glutamine metabolism and induction of immunosuppressive macrophages. Glutamine antagonists such as 6-diazo-5-oxo-L-norleucine (DON) and its prodrug JHU-083 can limit tumor growth, but their toxicity and immune cell selectivity remain suboptimal. Here, we conjugate DON with the macrophage-targeting moiety artesunate to develop WGF-T17 (T17), which blocks glutamine metabolism in macrophages. In vitro, T17 rewires macrophage metabolism toward glycolysis, inducing lactate buildup and histone lactylation, enhancing mitochondrial fission and phagocytic activity, and thereby reprogramming macrophages to an inflammatory state. In vivo, T17 controls tumor growth better than JHU-083 via macrophage-dependent pathways, and also increases the efficacy of immunotherapy, chemotherapy and anti-angiogenic therapy in female mice carrying subcutaneous CRC tumors. Our findings thus hint T17 as a promising treatment strategy for CRC by targeting macrophage glutamine metabolism to reverse immune suppression.
    DOI:  https://doi.org/10.1038/s41467-026-75208-0
  10. Cell Rep. 2026 Jul 09. pii: S2211-1247(26)00759-X. [Epub ahead of print]45(7): 117681
    Myeloid MMP14 couples extracellular proteolysis to inflammatory and metabolic remodeling during obesity.
    Long J Shao, Fathima Elizondo, Feng Gao, Elizabeth L Lieu, Bharati Reddi, Maryam Elizondo, Iqbal Mahmud, Kristin Eckel-Mahan, Philipp E Scherer, Xin Ge, Huaizhu Wu, Sean Hartig, Kai Sun.
      Macrophages orchestrate tissue remodeling, inflammation, and metabolic dysfunction in obesity, but the role of macrophage-intrinsic extracellular proteolysis in immunometabolic regulation remains unclear. Matrix metalloproteinase-14 (MMP14), a membrane-bound protease, is strongly induced during monocyte-to-macrophage differentiation and further elevated in adipose tissue macrophages from high-fat diet (HFD)-fed mice. Pharmacological inhibition or myeloid-specific deletion of Mmp14 impaired macrophage differentiation, proliferation, migration, phagocytosis, and inflammatory activation in response to obesity-associated adipose tissue signals. Mechanistically, MMP14 promoted inflammatory programming by increasing endotrophin generation and enhancing TLR4-NFκB signaling. MMP14 also reprogrammed macrophage lipid metabolism by suppressing lipolysis and promoting lipid accumulation, altering metabolic communication with neighboring cells. In vivo, myeloid-specific Mmp14 deletion protected mice from HFD-induced insulin resistance, dyslipidemia, hepatic steatosis, adipose inflammation, and fibrosis. These findings identify macrophage MMP14 as a key mediator linking extracellular matrix remodeling with inflammatory and metabolic dysfunction in obesity.
    Keywords:  CP: immunology; CP: metabolism; MMP14; inflammatory signaling; lipid metabolism; macrophages; metabolic adaptation
    DOI:  https://doi.org/10.1016/j.celrep.2026.117681
  11. Mater Today Bio. 2026 Aug;39 103399
    Reprogramming macrophage metabolism for cardiovascular therapy: From molecular pathways to precision nanomedicine.
    Huijun Guo, Yuji Xie, Yihui Wang, Yuan Song, Tian Peng, Junmin Zhang, Jing Liu, Ying Xu, Wenqian Wu, Jing Wang, Yali Yang, Li Zhang, Tang Gao, Mingxing Xie.
      Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, largely driven by chronic inflammation and inadequate tissue repair. As central orchestrators of immune homeostasis, macrophages undergo profound metabolic reprogramming that dictates whether inflammation is sustained or resolved. Glycolysis fuels the pro-inflammatory phenotype, whereas oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) support the reparative state. These metabolic transitions are governed by signaling pathways such as mammalian target of rapamycin (mTOR), nuclear factor-κB (NF-κB), peroxisome proliferator-activated receptor γ (PPAR-γ)/liver X receptor (LXR), and nuclear factor erythroid 2-related factor (NRF2), and further stabilized by epigenetic modifications that imprint long-term immunometabolic memory. This review integrates advances in signaling, metabolic, and epigenetic regulation of macrophage reprogramming in CVDs, with a focus on therapeutic strategies that modulate these axes. Particular attention is given to nanomedicine-based delivery systems that enable precise, controlled, and multi-level regulation of macrophage metabolism, overcoming the limitations of conventional therapies. By bridging macrophage immunometabolism with nanoscale intervention, this work outlines a framework for developing macrophage-centered therapeutics aimed at resolving inflammation, stabilizing atherosclerotic lesions, and enhancing cardiac repair, thereby advancing the translation of precision immunometabolic therapies in cardiovascular medicine.
    Keywords:  Cardiovascular diseases therapy; Epigenetic regulation; Immunometabolism; Macrophage metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103399
  12. bioRxiv. 2026 Jun 29. pii: 2026.06.24.734337. [Epub ahead of print]
    SIRT5-dependent regulation of ASL controls arginine metabolism and T cell function.
    Kim Han, Rachael J Klein, Kaiyuan Wu, Anna Chiara Russo, Allison M Meadows, Thomas C Recupero, Rahul Sharma, Anand K Gupta, Nathan T Brandes, Benjamin Schwarz, Michael N Sack.
      NAD⁺ supplementation blunts Th1 and Th17 inflammation, in part, through arginine metabolism-dependent regulation of mitochondrial energetics, redox balance and signal transduction. Whether the NAD + -dependent sirtuin deacylases contribute to this regulation is unknown. Here, we show that both SIRT1 and SIRT5 transcript levels are induced in CD4 + T cells in human participants following oral supplementation of the NAD + precursor nicotinamide riboside (NR). Among the sirtuin family members, SIRT5 rather than SIRT1 emerged as the predominant regulator of arginine and fumarate metabolism. Genetic depletion or pharmacologic inhibition of SIRT5 attenuated NR-mediated increases in arginine and fumarate and abolished the anti-inflammatory -effects of NR on Th1 and Th17 cytokine production. In contrast, the responses to exogenous arginine or citrulline supplementation were preserved, indicating that SIRT5 functions upstream of arginine biosynthesis. Metabolomic profiling further demonstrated that SIRT5 is required for NR-induced remodeling of the arginine biosynthetic pathway. Mechanistically, SIRT5 physically interacted with arginosuccinate lyase (ASL), promoted ASL-dependent arginine accumulation, and regulated ASL post-translational acylation, including glutarylation and malonylation. Loss of SIRT5 disrupted NR-mediated redox homeostasis, antioxidant gene expression, and cytokine suppression. Collectively, these findings identify SIRT5 as a critical mediator of NAD⁺ precursor-induced metabolic remodeling that links ASL-dependent arginine metabolism to redox balance and effector function in human CD4⁺ T cells.
    DOI:  https://doi.org/10.64898/2026.06.24.734337
  13. Nat Rev Nephrol. 2026 Jul 06.
    Metabolic determinants of autoimmune kidney diseases.
    Yogesh Scindia, Laurence Morel.
      Autoantibody-driven autoimmune diseases, such as systemic lupus erythematosus, frequently affect organs such as the kidney. The differentiation and function of pathogenic immune cells that drive these diseases are in part controlled by their metabolic programming. For diseases that affect the kidney, the response of kidney cells to immune-mediated injury is also in part controlled by metabolic changes. Immune cells that promote the production of autoantibodies and/or infiltrate the kidney in lupus nephritis are sustained by enhanced glycolysis and mitochondrial oxidation. These metabolic processes are also enhanced in the mesangial and glomerular endothelial cells of patients with lupus nephritis and animal models of lupus nephritis, which may contribute to tissue injury. Similar alterations in metabolic processes might be involved in other autoimmune diseases that affect the kidney, including IgA nephropathy and ANCA-associated vasculitis. Insights into metabolic changes that occur in the context of autoimmune-mediated kidney diseases might have therapeutic implications. Despite the complexity of metabolic alterations presented by specific immune and renal cells in these autoimmune diseases, targeting of glycolysis, mitochondrial oxidation or iron metabolism could offer novel opportunities to enhance existing treatments for autoimmune-mediated kidney injury.
    DOI:  https://doi.org/10.1038/s41581-026-01096-8
  14. NPJ Biofilms Microbiomes. 2026 Jul 07.
    Gut-derived cinnamic acid limits allergic airway inflammation via the SAT1-spermidine-eIF5A hypusination axis.
    Yujia He, Jing Liu, Zhihan Yang, Xiao Zhang, Yuanming Huang, Liqiong Song, Zhihong Ren.
      The gut-lung axis is a critical regulator of systemic immune homeostasis, however, the precise mechanisms linking gut-derived metabolites to distal airway inflammation remain incompletely understood. Here, we show that oral administration of viable Leuconostoc mesenteroides MY2024 engages a metabolite-host enzyme circuit that protects against allergic airway inflammation (AAI). Viable, but not heat-inactivated, MY2024 significantly attenuated ovalbumin (OVA)-induced Th2-driven eosinophilic asthma by suppressing pathogenic M2-like macrophage responses in the lung. Mechanistically, MY2024 increased gut-derived cinnamic acid (CA), which activated a colonic STAT1-SAT1 signaling axis to accelerate systemic spermidine catabolism. Reduced systemic spermidine availability was associated with reduced pulmonary eIF5A hypusination, a metabolic checkpoint known to support alternative macrophage activation. Notably, these protective effects and the associated metabolic reprogramming were preserved in microbiota-depleted mice, highlighting a direct bacterium-to-host metabolic axis. Together, our findings delineate a probiotic-metabolite-host enzyme circuit and identify colonic epithelial SAT1-dependent spermidine catabolism as a potential metabolic checkpoint for regulating type 2 AAI.
    DOI:  https://doi.org/10.1038/s41522-026-01089-2
  15. Front Immunol. 2026 ;17 1837643
    Cholinergic regulation of neuroinflammation: linking microglia, immunometabolism, and neuromodulation.
    Hui Guo, Ziyu Yang, Long Cheng.
      Neuroinflammation is increasingly recognized as a core pathological process in various neurological diseases, including neurodegenerative disorders, stroke, autoimmune demyelinating diseases, and acute brain dysfunction associated with systemic inflammation. Among its regulatory mechanisms, the cholinergic anti-inflammatory pathway links neural activity with immune regulation. However, its neurological relevance extends beyond the classical peripheral vagus nerve-mediated inflammatory reflex. Within the central nervous system, cholinergic signaling interacts with resident immune cells, particularly microglia, and influences inflammatory tone, neuronal vulnerability, and tissue repair. Recent advances in immunometabolism further suggest that metabolic reprogramming may bridge cholinergic signaling and microglial inflammatory phenotypes. In this review, we discuss the role of cholinergic regulation of neuroinflammation from three interrelated perspectives: microglia as the hub of core cells, immune metabolism as the basis of mechanism, and neural regulation as the frontier of transformation. We first reviewed the cholinergic system and its role in neuroimmune communication, then discussed how cholinergic signals shape microglial state and metabolic process, and finally evaluated its disease-specific evidence in Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis and acute inflammatory brain dysfunction. We will also discuss pharmacological and bioelectronic methods, including targeting cholinergic receptors and vagus nerve stimulation, as emerging therapeutic strategies. By integrating cholinergic biology, microglial heterogeneity, and metabolic reprogramming, this review proposes an updated framework for understanding neuroinflammation in neurology, and highlights the future opportunities for precise neuroimmune intervention.
    Keywords:  cholinergic signaling; immunometabolism; microglia; neuroinflammation; vagus nerve stimulation
    DOI:  https://doi.org/10.3389/fimmu.2026.1837643
  16. Nat Commun. 2026 Jul 04.
    CSF1R regulates monocyte subset differentiation and intracellular metabolism.
    Alexandre Gallerand, Johanna Merlin, Zakariya Caillot, Chloé Delaby, Elisa Bord, Jichang Han, Bastien Dolfi, Michael D Chang, Guilhem R Thierry, Alexia Castiglione, Sacha Grenet, Eloïse Goës, Maxime Franceschini, Gisèle Jarretou, Fairouz N Zair, Evy Boré, Florian Tuffin, David Dombrowicz, Giulia Chinetti, Rodolphe R Guinamard, Maxim N Artyomov, Abdelilah Wakkach, Didier F Pisani, Gwendalyn J Randolph, Adeline Bertola, Patrick Auberger, Arnaud Jacquel, David A Hume, Jesse W Williams, Marc Bajénoff, Jaap G Neels, Stoyan Ivanov.
      Monocytes are key circulating effectors of vascular homeostasis, innate immunity and inflammation. Following their generation in mouse bone marrow, classical (Ly6Chigh) monocytes are mobilized into the blood circulation where they mature into non-classical (Ly6Clow) patrolling monocytes or are recruited into peripheral tissues where they differentiate into tissue resident or inflammatory macrophages. Monocytes and macrophages express CSF1R (CD115), the receptor for lineage-specific growth factors CSF1 and IL-34. Here, we report that acute CSF1R blockade or genetic deletion negatively interferes with monocyte intracellular metabolism and reduces blood Ly6Clow monocytes in part by blunting differentiation of Ly6Chigh monocytes. Based upon lineage-specific deletion of Glutamine-Fructose-6-Phosphate Transaminase 1 (GFPT1), the hexosamine biosynthetic pathway (HBP) is identified as an important regulator of CSF1R expression and monocyte subsets. Inhibition of receptor tyrosine kinases CSF1R and FLT3 rewires and partially impairs metabolic activity in human monocytes. Our findings provide insights into the link between CSF1R signaling, metabolic regulation, and monocyte survival and differentiation.
    DOI:  https://doi.org/10.1038/s41467-026-75263-7
  17. Int Immunopharmacol. 2026 Jul 07. pii: S1567-5769(26)00915-X. [Epub ahead of print]186 117069
    Dioscin suppresses colitis-associated colorectal tumorigenesis by inhibiting PPARγ-mediated fatty acid oxidation in TAMs.
    Jing Xun, Xiaolin Jiang, Jinlu Zhang, Bin Liu, Yanli Wang, Lixiu Ge, Minghui Chen, Lijuan Hu, Yingdi Han, Shimin Yang, Aimin Zhang, Qi Zhang.
       BACKGROUND: Chronic inflammation plays a key role in colorectal carcinogenesis, where tumor-associated macrophages (TAMs) critically promote tumor progression. Metabolic reprogramming of TAMs, particularly through the modulation of fatty acid oxidation (FAO), represents a promising therapeutic strategy; however, effective agents remain to be identified. Although the natural compound dioscin exhibits anti-tumor properties, its ability to regulate TAM plasticity and metabolism in colitis-associated colorectal cancer (CAC) remains unclear.
    METHODS: A mouse model of CAC was established using azoxymethane/dextran sulfate sodium (AOM/DSS). Mice were treated with dioscin, and tumor development was monitored. Bone marrow-derived macrophages were polarized into TAMs, and the effects of dioscin on polarization and metabolism were evaluated by flow cytometry, immunohistochemistry, Seahorse analysis, and biochemical assays. Systemic macrophage depletion assay via clodronate liposomes validated the necessity of TAMs. Molecular docking, CETSA, and DARTS assays identified the direct target of dioscin. Pharmacological or genetic modulation of PPARγ confirmed mechanistic necessity.
    RESULTS: Dioscin significantly suppressed colorectal tumorigenesis in vivo. This efficacy was abolished upon macrophage depletion, confirming TAMs dependency. Dioscin modulated the TAMs polarization by primarily suppressing the M2 phenotype, leading to an increase in the M1/M2 ratio. Mechanistically, dioscin directly bound to PPARγ, suppressing its expression and downstream CPT1A-mediated FAO. Seahorse analysis revealed impaired spare respiratory capacity. Notably, while FAO inhibition coincided with increased lactate production, glycolytic flux and gene expression remained unaltered. Both pharmacological activation and genetic ablation of PPARγ abrogated dioscin-induced FAO inhibition and TAMs polarization.
    CONCLUSION: Our study demonstrates that dioscin inhibits colorectal carcinogenesis by directly targeting PPARγ in TAMs, leading to the suppression of FAO and a consequent reduction in M2 polarization. These findings establish dioscin as a promising candidate for future therapeutic strategies targeting the immunosuppressive tumor microenvironment.
    Keywords:  Colitis-associated colorectal cancer; Dioscin; Fatty acid oxidation; PPARγ; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.intimp.2026.117069
  18. Trends Immunol. 2026 Jul 08. pii: S1471-4906(26)00161-4. [Epub ahead of print]
    Adenosine as a metabolic checkpoint in CD8+ T cell dysfunction.
    Arden O Edgerton, Mauricio J Reginato, Michele A Kutzler, Eilas K Haddad.
      CD8+ T cell dysfunction, characterized by impaired effector function, proliferative capacity, and sustained inhibitory receptor expression, limits immune control in both cancer and chronic viral infections. Despite arising from distinct disease processes, these conditions induce a shared state of CD8+ T cell dysfunction, suggesting convergence on common regulatory pathways. Adenosine (ADO), an immunosuppressive purine metabolite generated through extracellular ATP catabolism, has emerged as a context-integrating metabolic checkpoint that regulates immune responses in response to tissue stress and inflammation. Across tumors and HIV, dysregulated ADO signaling reinforces checkpoint pathways and stabilizes dysfunctional CD8+ T cell states. In this review, we examine how the ADO-adenosine deaminase-1 axis shapes CD8+ T cell dysfunction across disease contexts and discuss its potential as a broadly applicable target for immune restoration.
    Keywords:  ADA-1; CD8+ T cells; T cell dysfunction; adenosine; chronic infection; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.it.2026.06.005
  19. Front Immunol. 2026 ;17 1806060
    Restoring immune homeostasis in the spinal microenvironment: targeting mechano-inflammation and immunometabolic reprogramming.
    Zhichao Chen, Junfeng Zeng, Zhiwei Zhang, Zhi Zheng.
      Chronic inflammatory diseases of the spine, typified by axial spondyloarthritis (axSpA) and intervertebral disc degeneration (IDD), impose a substantial burden through refractory pain and irreversible structural remodelling (pathological ossification or fibrosis). Although current anti-inflammatory therapies can alleviate symptoms, their capacity to arrest structural deterioration remains limited, underscoring the constraints of approaches that target inflammatory cytokines in isolation. This therapeutic intractability is rooted in the distinctive spinal microenvironment: high mechanical loading at the enthesis and the hypoxic niche of the intervertebral disc (IVD), through mechano-inflammatory coupling and maladaptive metabolic adaptation, actively drive pathological reprogramming of immune cells and create a barrier to the restoration of homeostasis. In this Review, we dissect the multidimensional crosstalk among biomechanics, metabolism and immunity, and delineate the central roles of Human leukocyte antigen B27 (HLA-B27) associated stress, metabolic reprogramming, and osteo-immune crosstalk in sustaining chronic inflammation. On this basis, we propose a paradigm shift from suppressing downstream mediators to modulating upstream microenvironments. We suggest that targeting metabolic checkpoints, interrupting mechanotransduction, and applying epigenetic interventions may promote inflammatory resolution and reset matrix homeostasis, thereby offering new strategies to restore spinal immune equilibrium and prevent structural failure.
    Keywords:  axial spondyloarthritis; epigenetic memory; immunometabolism; intervertebral disc degeneration; spinal microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1806060
  20. Research (Wash D C). 2026 ;9 1347
    Type 2 Inflammatory Diseases: The Crossroads of Immunity and Metabolism.
    Lin Chen, Zhou-Xian Pan, Zi-Qi Ma, Yu-Xuan Jin, Yi Ru, Pei-Song Gao, Cheng Yang, Shi-Su Zhao, Jing Zhang, Ji-Han Li, Christopher Chang, Yu-Zheng Zhao, Jin-Lyu Sun.
      The understanding of type 2 inflammatory diseases is undergoing a paradigm shift from "immune imbalance" toward "immune-metabolic crosstalk". Energy metabolism not only fuels immune responses but also fundamentally dictates the functional phenotypes of immune cells through metabolic reprogramming. By systematically integrating metabolic programming data of key immune cells across diverse tissues (skin, gut, nasal, and ocular mucosa), this review constructs a cross-disease "metabolism-signaling network" atlas. The synthesis highlights that glycolysis and mTORC1 signaling are predominantly coupled with the pro-inflammatory outputs of Th2 cells and ILC2s, whereas fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) sustain the homeostasis of Tregs and M2-like macrophages. Furthermore, this review characterizes how the tryptophan, glutamine, and arginine pathways fine-tune the immune tolerance boundary via the IDO-AhR-mTOR axis. We also elucidate a conserved inter-organ "hypoxia-HIF-1α-lactylation" axis, which, in conjunction with tissue-specific metabolic branches (e.g., the ceramide pathway in the skin, the SCFA circuit in the gut, and the lactate-GPR81 loop in the mucosa), collectively sculpts local microenvironments and remodeling trajectories. Ultimately, a novel diagnostic and therapeutic framework centered on metabolic phenotyping is proposed, providing prospective insights into targeting metabolic checkpoints for precision immunotherapy in type 2 inflammation.
    DOI:  https://doi.org/10.34133/research.1347
  21. Neurosci Bull. 2026 Jul 07.
    Dysfunctional Mitochondria in Microglia Drive Cognitive Aging and Neurodegeneration via cGAS-STING.
    Guanqin Ma, Erlin Wang, Xiaoxu Yan, Xiang-Xiong Xu, Xiaohong Li, Xueling Ma, Wan-Hua Yang, Jianxiong Zeng, Xiaochun Xie.
      Mitochondrial dysfunction induces metabolic dysregulation in immune cells that is etiologically associated with age-related brain disorders. However, how dysfunctional mitochondria in microglia-the brain-resident immune cells-initially affect neurological function remains incompletely understood. Here, we demonstrate that dysfunctional mitochondria in microglia, induced by the conditional knockout of mitochondrial transcription factor A, act as triggers of metabolic dysregulation, cognitive aging, and neurodegeneration in adult mice. Notably, this metabolic disturbance induces a microglial transition to states associated with neuroinflammatory activation and neurodegenerative disease, thereby triggering multiple layers of pathological cascade reactions among other brain cell types and shaping a neuroinflammaging state at single-cell resolution. Mechanistically, mitochondrial dysfunction activates the innate immune cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which mediates immune sensing of cytosolic DNA in microglia and contributes to inflammaging. We further present evidence that combined treatment aimed at restoring metabolic homeostasis and inhibiting neuroinflammatory cGAS-STING partially rescues age-related neurological dysfunction in mice. Collectively, our findings reveal a link between mitochondrial dysfunction in microglia and cognitive aging, underscoring the significance of tightly regulated metabolism in age-associated neurological diseases.
    Keywords:  Microglia; Mitochondrial dysregulation; Neurodegeneration; Neuroinflammaging; cGAS–STING
    DOI:  https://doi.org/10.1007/s12264-026-01657-8
  22. Exp Mol Med. 2026 Jul 06.
    Adipocyte OX40L promotes adipose T cell activation and insulin resistance in obesity.
    Jianfeng Song, Qin Zeng, Yayi Jiao, Xiaoxiao Sun, Limin Xie, Jingpei Qiu, Yujin Ding, Wanyu Hu, Fanqi Wang, Biling Huang, Wuqian Mai, Ying Mei, Dandan Wang, Lan Xie, Xiang Xiao, Wei Liu, Willa A Hsueh, Xian C Li, Tuo Deng.
      T cells contribute critically to obesity-induced adipose inflammation and insulin resistance, yet the co-stimulatory signals that govern their activation in adipose tissue remain unclear. Here, we systematically profile co-stimulatory molecules in adipocytes and adipose tissue macrophages and identify OX40 ligand (OX40L) as the most robustly upregulated in obesity. OX40L is also elevated in adipocytes from obese humans. Although macrophage-specific OX40L deletion has no metabolic impact, global OX40 deficiency or adipocyte-specific OX40L deletion reduces Th1 cell accumulation in visceral adipose tissue, attenuates inflammation and improves insulin sensitivity without affecting adiposity. These benefits are reversed by Th1 cell transfer. Therapeutic blockade of OX40L with a neutralizing antibody mimics the protective effects of genetic deletion. Our findings identify adipocyte-derived OX40L as a critical mediator of obesity-associated immune dysfunction and establish it as a targetable checkpoint for tissue-specific immunotherapy in metabolic disease.
    DOI:  https://doi.org/10.1038/s12276-026-01770-8
  23. Int J Oral Sci. 2026 Jul 09. pii: 49. [Epub ahead of print]18(1):
    CHAC2-mediated glutathione metabolic reprogramming drives N1 polarization of bone marrow neutrophils and exacerbates inflammatory comorbidities.
    Yuting Niu, Yuman Li, Shiyu Sun, Chenyu Deng, Fan He, Yiming Chen, Tiansong Xu, Zhewen Hu, Gai Yang, Leran Li, Boon Chin Heng, Yan Lv, Ying Huang, Xuliang Deng.
      The proinflammatory (N1) polarization of bone marrow (BM) neutrophils, driven by central immune remodeling in response to peripheral inflammation, plays a critical role in propagating localized inflammatory conditions, such as periodontitis, to systemic levels. Although this process involves metabolic reprogramming, the specific underlying metabolic mechanisms of neutrophil N1 polarization within the periodontitis-modified BM niche remain poorly defined. Integrated transcriptomic and metabolomic analyses in this study revealed that periodontitis reprograms intracellular glutathione (GSH) metabolism in BM neutrophils, facilitating their N1 polarization. Central to this mechanism is the upregulation of Chac2, an enzyme that promotes GSH accumulation. This enhancement is accompanied by elevated GSH redox cycling, which supports sustained ROS production and NET formation, thereby amplifying inflammatory responses. We further identified type I interferon (IFN-I) signaling as a key upstream regulator that induces Chac2 expression and drives metabolic reprogramming. Importantly, the intraosseous delivery of AAV-delivered Chac2 shRNA in db/db mice with periodontitis markedly reduced neutrophil-aggravated systemic inflammatory comorbidity symptoms and improved glycemic control, underscoring the functional relevance of this pathway in diabetic comorbidity. Together, these findings thus delineate the IFN-I-Chac2-GSH axis as a core signaling mechanism regulating neutrophil N1 polarization in the BM niche, providing new insights into how periodontal inflammation reprograms immune functions at the systemic level. This study thus broadens the conceptual framework of neutrophil immunometabolism and proposes targeting the Chac2-GSH axis as a potential therapeutic strategy for systemic comorbidities associated with periodontitis.
    DOI:  https://doi.org/10.1038/s41368-026-00451-6
  24. Int J Mol Med. 2026 Sep;pii: 250. [Epub ahead of print]58(3):
    Phenylalanine exacerbates psoriasiform inflammation through NF‑κB‑mediated dendritic cell activation and Th17 polarization.
    Yaohan Xu, Jing Pan, Jie Chen, Yutao Zhu, Miaolian Cai, Zeyu Ma, Siji Chen, Tianze Yu, Yushu Wei, Jingying Pan, Kunliang Luo, Yinjing Song, Stijn Van Der Veen, Hao Cheng.
      Metabolic dysregulation has been increasingly recognized as a key driver in the pathogenesis of psoriasis; however, the specific mechanistic contributions of amino acid perturbations remain poorly understood. The present study, through comprehensive metabolomic profiling, observed a marked accumulation of phenylalanine in both the circulation and skin lesions of psoriatic mice. Notably, a high‑phenylalanine diet exacerbated psoriasiform skin inflammation of imiquimod‑induced psoriasis, whereas dietary restriction of phenylalanine or administration of L‑type amino acid transporter inhibitors effectively alleviated skin inflammation. Mechanistically, transcriptome sequencing of dendritic cells identified phenylalanine as a potent metabolic trigger. The present analysis revealed that high phenylalanine levels alone significantly elevated the baseline expression of notable pro‑inflammatory cytokines and this inflammatory response was further amplified in the presence of imiquimod. The present study determined that this pro‑inflammatory effect was mediated through the NF‑κB signaling pathway, which subsequently promoted the differentiation of T helper 17 cells. Collectively, the present findings uncovered a previously unrecognized metabolic checkpoint in psoriasis and suggested that restriction of phenylalanine represents a promising, non‑toxic adjunctive therapeutic strategy for the clinical management of psoriasis.
    Keywords:  amino acid metabolism; dendritic cells; inflammatory cytokines; phenylalanine; psoriasis
    DOI:  https://doi.org/10.3892/ijmm.2026.5921
  25. J Infect Dev Ctries. 2026 Jun 30. 20(6): 886-895
    USP18-driven macrophage M2 polarization through fatty acid β-oxidation inhibits immune responses induced by RSV infection.
    Dannv Yang, Liyan Zhao, Li Liu, Jian Zhang, Jingwen Wang.
       INTRODUCTION: Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory infections in infants under six months, with limited treatment options available. Macrophages play a pivotal role in antiviral immunity, where their polarization state directly modulates immune responses.
    METHODOLOGY: The expression changes of ubiquitin-specific protease 18 (USP18) in RSV-infected samples were analyzed through the Gene Expression Omnibus database. An RSV infection model was established in C57BL/6 mice, and USP18 expression in lung tissues was measured by quantitative polymerase chain reaction (qPCR). Adenovirus-mediated USP18 knockdown was performed via tail vein injection, and its effects on immune cells were assessed using enzyme-linked immunosorbent assay (ELISA) and qPCR. THP-1 macrophage models with USP18 overexpression and knockdown were constructed. The effects of USP18 on macrophage polarization, immune function, and fatty acid β-oxidation during RSV infection were evaluated using immunofluorescence, ELISA, fatty acid oxidation (FAO) assays, boron-dipyrromethene (BODIPY) staining, and Western blot.
    RESULTS: USP18 was markedly overexpressed in RSV-infected samples. USP18 knockdown in mice alleviated lung damage, reduced M2 macrophage markers, and enhanced CD8+ T cell activity. Cellular experiments demonstrated that USP18 promotes M2 macrophage polarization by enhancing fatty acid β-oxidation and regulating the expression of related enzymes, including ACLY, FASN, and ACC1. Elevated USP18 in macrophages during RSV infection inhibits CD8+ T cell activation, contributing to immune suppression. These effects were reversible with FAO inhibitors.
    CONCLUSIONS: USP18 upregulation in RSV-infected cells induces M2 macrophage polarization via fatty acid β-oxidation, thereby promoting immune suppression.
    Keywords:  USP1; fatty acid β-oxidation; macrophages; respiratory syncytial virus
    DOI:  https://doi.org/10.3855/jidc.21782
  26. Br J Pharmacol. 2026 Jul 06.
    Tangeretin ameliorates sepsis-induced neurocognitive impairment in adult male mice by suppressing Akt-driven glycolytic reprogramming and neuroinflammation.
    Juexian Wei, Haifeng Mao, Hengzong Mo, Yixin Chen, Ehua Deng, Aijia Zhong, Xiaoyan Tang, Senwen Liu, Shiqing Zheng, Haojun Liao, Huilin Jiang, Shao-Peng Lin, Xiaohui Chen.
       BACKGROUND AND PURPOSE: Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, frequently leads to long-term cognitive impairment. Tangeretin, a polymethoxylated citrus flavonoid, has neuroactive and anti-inflammatory properties. We investigated whether tangeretin protects against sepsis-associated neurocognitive deficits and delineated the underlying mechanisms, focusing on Akt signalling and microglial metabolism.
    EXPERIMENTAL APPROACH: Sepsis was induced by caecal ligation and puncture in mice. Tangeretin (15 or 30 mg·kg-1·day-1, intraperitoneal) was initiated immediately after surgery and maintained throughout the study. Cognitive function was assessed by Morris water maze and novel object recognition. Hippocampal microglial activation and neuroinflammation were quantified. In vitro, BV2 cells and primary microglia were exposed to lipopolysaccharide (LPS, 1 μg·ml-1) with/without tangeretin (40 μM) to measure cytokine production, migration and Akt activity. Direct tangeretin-Akt interaction was tested by surface plasmon resonance and cellular thermal shift assay. Metabolic readouts focused on glycolysis.
    KEY RESULTS: Tangeretin improved sepsis-induced cognitive deficits, decreased hippocampal microglial activation, and lowered proinflammatory cytokine levels and microglial migration. It exerted anti-inflammatory effects via inhibition of the Akt pathway, and pharmacological Akt activation blocked these effects. Surface plasmon resonance and cellular thermal shift assay showed hat tangeretin binds Akt. Metabolically, tangeretin reduced LPS-induced glycolysis (decreased extracellular acidification rate and glycolytic capacity), consistent with diminished Akt phosphorylation and microglial activation.
    CONCLUSION AND IMPLICATIONS: Tangeretin mitigates sepsis-associated neuroinflammation and cognitive impairment by targeting microglial Akt signalling and restraining glycolytic reprogramming. These data support tangeretin as a mechanistically informed candidate for adjunctive therapy in sepsis-related neurocognitive dysfunction.
    Keywords:  cognitive deficits; glycolysis; microglia; sepsis; serine–threonine kinase; tangeretin
    DOI:  https://doi.org/10.1111/bph.70477
  27. Nat Commun. 2026 Jul 06.
    Dipeptidyl peptidase 3 sets the threshold for immune activation and survival during experimental bacterial infection.
    Amanda Facoetti, Luca Lambroia, Elena Fontana, Federico Nicchiotti, Maria Lucia Schiavone, Dario Strina, Raffaello Viganò, Francesca Brambilla, Davide Mangioni, Samantha Scaramuzza, Sara Mallia, Marcella Bonanomi, Andrea Farini, Mirella Meregalli, Debora Mostosi, Giuseppe Rocca, Ciro Menale, Cecilia Garlanda, Antonio Muscatello, Alessandra Bandera, Daniela Gaglio, Cristina Sobacchi, Yvan Torrente, Pierluigi Mauri, Dario Di Silvestre, Clelia Peano, Francesca Granucci, Veronica Marrella, Barbara Cassani.
      Effective host defense requires coordinated regulation of immune activation, metabolism, and redox balance, yet how these processes are integrated remains unclear. Here, we identify dipeptidyl peptidase 3 (Dpp3) as a regulator of immune activation thresholds during bacterial infection. Dpp3-/- mice display enhanced resistance to Klebsiella pneumoniae, with early divergence in bacterial burden, improved survival, preserved tissue architecture, and reduced systemic inflammation. Adoptive transfer experiments demonstrate that Dpp3-deficient immune cells are sufficient to confer protection, indicating a cell-intrinsic effect. Mechanistically, Dpp3 deficiency impairs inducible Nrf2 stabilization, resulting in amplified ROS accumulation and enhanced NF-κB-associated responses. Integrated metabolomic, bioenergetic, and proteomic analyses reveal coordinated mitochondrial remodeling and activation of inflammatory signaling networks, consistent with a metabolically primed immune state. Collectively, these findings establish Dpp3 as a systems-level regulator integrating redox control and immunometabolism to calibrate antimicrobial responses during infection.
    DOI:  https://doi.org/10.1038/s41467-026-74740-3
  28. Biomed Res Int. 2026 ;2026(1): e1172509
    Immunometabolic Reprogramming of Fibroblastic Reticular Cells in the Tumor Immune Microenvironment.
    Tian Tian, Huimin Liu, Peiyan Liu, Shumin Ye, Yudi Wu, Jun Zhou.
      Fibroblastic reticular cells (FRCs), as core stromal cells in secondary lymphoid tissues and the tumor immune microenvironment (TIME), undergo significant immunometabolic reprogramming, which regulates antitumor immune responses. This structured narrative review summarizes the immunometabolic reprogramming of FRCs across various cancers, emphasizing glucose metabolism, lipid remodeling, and amino acid metabolism in lung cancer, breast cancer, gastric cancer, lymphoma, head and neck tumors, and melanoma. Under hypoxia, nutrient stress, and inflammatory stimulation, FRCs enhance glycolysis, alter fatty acid synthesis/oxidation, and disrupt amino acid metabolism, leading to immunosuppressive metabolite secretion, cytokine profile changes, and the formation of immune niches. Understanding these cancer-specific molecular mechanisms can inform targeted immunometabolic therapies.
    Keywords:  fibroblastic reticular cell; immunometabolic reprogramming; multiple cancer types; tumor immune microenvironment
    DOI:  https://doi.org/10.1155/bmri/1172509
  29. Dev Comp Immunol. 2026 Jul 08. pii: S0145-305X(26)00137-0. [Epub ahead of print] 105681
    Hemocyanin is associated with GAPDH-related glycolytic metabolism during anti-Vibrio responses in Penaeus vannamei.
    Jiashun Guo, Yantang Zou, Qiaofang Hong, Baiqiao Chen, Ziyi Zhang, Xiuli Chen, Yongzhen Zhao, Shulong Guan, Yueling Zhang, Zhihong Zheng.
      Immunometabolic reprogramming is a hallmark of host defense. Recent studies have shown that hemocyanin regulates the tricarboxylic acid (TCA) cycle in shrimp to enhance immune competence, yet its role in glycolytic regulation remains unclear. Here, we show that RNA interference-mediated silencing of hemocyanin in Penaeus vannamei markedly reduces the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a key glycolytic enzyme. Hemocyanin knockdown also decreases GAPDH protein abundance and enzymatic activity, accompanied by reduced levels of 1,3-bisphosphoglycerate and NADH. Although no direct physical interaction between hemocyanin and GAPDH was detected, co-expression of PvHMC was associated with increased total GAPDH enzymatic activity in the heterologous HEK-293T system, suggesting an indirect functional association. Upon pathogen challenge, both hemocyanin and GAPDH responded dynamically, and exogenous NADH supplementation partially restored the expression of representative glycolytic and TCA-cycle enzymes in hemocyanin-silenced shrimp. Importantly, NADH supplementation reduced Vibrio parahaemolyticus burden and improved host survival after infection. Together, these findings support a model linking hemocyanin with GAPDH-related glycolytic metabolism and NADH homeostasis.
    Keywords:  Anti-Vibrio immunity; GAPDH; Glycolysis; Hemocyanin; NADH; Penaeus vannamei
    DOI:  https://doi.org/10.1016/j.dci.2026.105681
  30. Int J Tryptophan Res. 2026 ;19 11786469261461119
    Latent Cerebral Toxoplasma Gondii Infection Induces the Kynurenine Pathway and Production of Neurotoxic Metabolites.
    Amir Mohamed Kezai, Mahmoudou Ba, Benjamin Hennart, Anais Jacquemart, Emilie Faivre, David Blum, Delphine Allorge, Sabrina Marion.
      The kynurenine pathway (KP) has been implicated in a broad range of neurological disorders. KP activation in brain resident immune cells, including astrocytes and microglia, contributes to the release of neuroactive metabolites with strong impact on neuronal functions. KP activation is triggered by inflammatory cues, however the contribution of chronic brain infections on KP activation remains poorly explored. Toxoplasmosis is 1 of the most common infections caused by protozoan parasites. Infection of immuno-competent individuals is characterized by bradyzoite-containing cyst development in neurons, leading to life-long chronic infections. Control of latent toxoplasmosis relies on an IL-12-induced T-cell derived IFNγ response, and results in a sustained inflammation of the brain characterized by activation of recruited and resident immune cells. Here, we investigated a possible link between induction of a persistent neuroinflammation induced by Toxoplasma gondii long-term infection, modulation of the KP and production of key neuroactive metabolites. Our findings demonstrate that chronic infection with either of 2 Toxoplasma gondii strains- causing encephalitis and the other inducing latency-leads to sustained activation of the KP, resulting in increased production of quinolinic acid, an excitotoxic metabolite known to have detrimental effects on neurons.
    Keywords:  kynurenine pathway; latent toxoplasmosis; neuroinflammation; quinolinic acid
    DOI:  https://doi.org/10.1177/11786469261461119
  31. Int J Oncol. 2026 Sep;pii: 99. [Epub ahead of print]69(3):
    Glycolysis‑driven immunosuppression in gastric cancer: Metabolic crosstalk between tumor cells and the immune microenvironment (Review).
    Bo Zhang, Lihan Shang, Ziyu Kuang, Chaoran Wang, Bingsheng Sun, Fanming Kong.
      Gastric cancer (GC) remains a major cause of cancer‑related mortality worldwide, and only a subset of patients achieves durable benefit from immune checkpoint blockade (ICB). This suggests that non‑genomic barriers within the tumor microenvironment (TME) substantially limit antitumor immunity. Increasing evidence indicates that tumor‑intrinsic glycolytic reprogramming and lactate accumulation contribute to this immune resistance. Oncogenic signaling, hypoxia‑inducible factor‑1α (HIF‑1α), phosphoinositide 3‑kinase/protein kinase B/mechanistic target of rapamycin (mTOR) pathways and noncoding RNA networks promote the expression of glycolytic enzymes and lactate transporters, including hexokinase 2, 6‑phosphofructo‑2‑kinase/fructose‑2,6‑biphosphatase 3 (PFKFB3), pyruvate kinase M2, lactate dehydrogenase A (LDHA) and monocarboxylate transporters, thereby establishing a glycolysis‑high, lactate‑rich TME. Within this metabolic niche, lactate functions as a bioactive mediator that impairs dendritic cell differentiation and cross‑priming, weakens cytotoxic T‑cell and natural killer‑cell activity, and promotes M2‑like macrophages and myeloid‑derived suppressor cells through hydroxycarboxylic acid receptor 1/G protein‑coupled receptor 81‑dependent signaling and histone lactylation. Cancer‑associated fibroblasts and mesenchymal stem/stromal cells further reinforce this state through glycolysis, lactate shuttling, cytokine secretion, extracellular matrix remodeling and exosome‑mediated transfer of glycolysis‑promoting noncoding RNAs. These interactions generate spatially organized immunometabolic niches characterized by lactate accumulation, stromal remodeling, abnormal angiogenesis and poor CD8+ T‑cell infiltration. The present review summarizes the molecular drivers of glycolytic reprogramming in GC, the mechanisms by which lactate‑centered crosstalk reshapes stromal and immune compartments, and emerging therapeutic strategies targeting LDHA/monocarboxylate transporter 4, PFKFB3, HIF‑1α/mTOR, epigenetic regulators and repurposed metabolic drugs in combination with programmed death‑1/programmed death‑ligand 1 blockade. It is also discussed how fluorine‑18 fluorodeoxyglucose positron emission tomography/computed tomography, radiomics, glycolysis‑ and lactylation‑related gene signatures, exosomal biomarkers and dynamic metabolic monitoring may support patient stratification and response prediction. Viewing selected GC subtypes through a glycolysis‑centered immunometabolic framework may help guide the rational integration of metabolic and immune interventions to overcome metabolically protected, ICB‑refractory disease.
    Keywords:  dendritic cells; gastric cancer; glycolysis; immune checkpoint blockade; lactate; metabolic imaging; tumor immunometabolism; tumor microenvironment
    DOI:  https://doi.org/10.3892/ijo.2026.5912
  32. bioRxiv. 2026 Jul 01. pii: 2026.06.26.734825. [Epub ahead of print]
    Mitochondrial STAT3-mediated suppression of apoptosis constrains antimycobacterial immunity.
    C J Mabry, A K Coleman, M H Smith, S L Hahn, T M Newbolt, M J Chapman, L W Stranahan, C G Weindel, K L Patrick, R O Watson.
      Maintenance of mitochondrial homeostasis is required to balance the host-pathogen interface during Mycobacterium tuberculosis (Mtb) infection. Here, we identify the non-canonical TRIM family member Trim14 as a critical regulator of mitochondrial integrity in Mtb-infected macrophages. Specifically, we demonstrate that Trim14 preserves mitochondrial membrane polarization and limits macrophage apoptosis by controlling phosphorylation and mitochondrial targeting of Stat3. When targeted to mitochondria, Stat3 restricts opening of the mitochondrial permeability transition pore, which raises the macrophage threshold for apoptotic commitment. In vivo , loss of Trim14 enhances apoptosis of macrophages and dendritic cells, leading to augmented antimycobacterial immunity marked by increased CD8 + T cell activation and effector function. Together, these findings define a Trim14-mitochondrial Stat3 axis that suppresses host-protective apoptosis during Mtb infection and pinpoint mitochondrial Stat3 as a potential target for therapies aimed at boosting antimycobacterial immunity.
    HIGHLIGHTS: Trim14 raises the apoptotic threshold in Mtb-infected macrophages.Trim14 controls phosphorylation and mitochondrial targeting of Stat3.Reduced mitochondrial Stat3 promotes mPTP opening and apoptotic commitment. Trim14 deficiency enhances apoptosis, CD8 + T cell immunity, and Mtb resistance.
    DOI:  https://doi.org/10.64898/2026.06.26.734825
  33. J Transl Med. 2026 Jul 08.
    Disrupting the adiposopathy-inflammation loop: a translational immunometabolic framework for inflammatory disease.
    Salvatore Corrao.
      Adipose tissue dysfunction is increasingly recognized as a biologically active contributor to chronic inflammatory disease beyond its traditional role in energy storage. In the context of obesity, adiposopathy is characterized by persistent immunometabolic alterations involving adipokine dysregulation, macrophage infiltration, insulin resistance, and chronic low-grade inflammation. These processes intersect with inflammatory signaling pathways central to immune-mediated diseases, supporting the concept of an immunometabolic phenotype in which metabolic dysfunction and immune activation converge to influence disease expression and therapeutic responsiveness. This framework does not merely restate the association between obesity and inflammation; rather, it proposes adiposopathy as a measurable immunometabolic state that may amplify inflammatory signaling, influence therapeutic responsiveness, and identify patients in whom combined metabolic-immune targeting could be biologically rational. The recent TOGETHER-PsA trial provides an important clinical proof of concept for this framework, demonstrating that adding tirzepatide to IL-17 inhibition achieved greater disease control than cytokine blockade alone in psoriatic arthritis among those with overweight or obesity. Rather than representing definitive evidence of disease modification, these findings suggest that targeting adipose tissue dysfunction may influence inflammatory disease activity in selected contexts. Extrapolation from this single, disease-specific trial should therefore be regarded as hypothesis-generating and requires validation in other inflammatory conditions. Emerging evidence further indicates that incretin-based therapies may exert anti-inflammatory effects extending beyond weight reduction alone. Experimental studies support potential direct immunomodulatory roles of GLP-1 and GIP receptor signaling within immune and myeloid cell populations, although the relative contribution of direct receptor-mediated pathways versus secondary metabolic improvement remains incompletely understood. Within this emerging translational framework, adiposopathy may represent a therapeutically actionable upstream regulator of inflammatory signaling. Further mechanistic and clinical studies are needed to clarify how modulation of adipose tissue dysfunction may complement conventional immune-targeted therapies across chronic inflammatory diseases.
    Keywords:  Adiposopathy; Chronic inflammation; GLP-1/GIP receptor signaling; Immunometabolism; Incretin-based therapies; Obesity-related inflammation; Psoriatic arthritis; Tirzepatide; Translational medicine; Visceral adiposity
    DOI:  https://doi.org/10.1186/s12967-026-08564-6
  34. Cell Host Microbe. 2026 Jul 08. pii: S1931-3128(26)00271-4. [Epub ahead of print]34(7): 1151-1153
    An acidic welcome: How microbial metabolites keep fungi in line.
    Marienela Y Heredia, Gustavo Caballero-Flores.
      Microbiota-derived metabolites shape gut microbial ecology, but how they limit expansion of potentially pathogenic fungi remains elusive. In this Cell Host & Microbe issue, Mishra et al. and Yasuma-Mitobe et al. identify short-chain fatty acids as antifungal metabolites promoting colonization resistance against Candida species via intracellular acidification and metabolic stress.
    DOI:  https://doi.org/10.1016/j.chom.2026.06.011
  35. Immunol Invest. 2026 Jul 09. 1-40
    Crosstalk Between Immunometabolic Pathways in Non-Small Cell Lung Cancer.
    Riya Khilwani, Pooja Gulhane, Manasi Tukrul, Divya Rani, Gautam Kumar, Swati Goswami, Shailza Singh.
       BACKGROUND: Immunometabolic reprogramming has emerged as a key regulator of both innate and adaptive immune responses. In NSCLC, immunometabolism not only sustains tumor growth but also enables immune evasion through altering the immune cell behavior within the tumor microenvironment. Despite multiple signaling pathways having been implicated in the process, the integration of inflammatory cytokines and metabolic signaling underlying autophagy dysregulation in NSCLC remains unexplored.
    OBJECTIVE: From a cellular perspective, the review summarizes the immunometabolic and regulatory functions of IL-6 and IL-17 in inflammaphagy and their integration into immunometabolic networks. The conserved contributions of key regulatory pathways, including BMP, DUSP, FOXO, SPROUTY, and STING, in shaping immune cell metabolism and tumor progression were also underscored.
    METHODS: A narrative review of recent literature was performed focusing on integrating findings from experimental and clinical studies to construct a unified framework defining cytokine interactions, immune metabolism, and tumor progression.
    RESULTS: IL-6 and IL-17 are critical regulators for metabolically adapting tumor cells while influencing macrophages, T-cells, neutrophils, and other immune subsets towards attaining a metabolic shift. Additionally, conserved trajectories of BMP, DUSP, FOXO, SPROUTY, and STING modulate metabolic homeostasis for tumor development, highlighting their crosstalk between inflammatory and metabolic networks.
    CONCLUSION: Advances in understanding the interconnected role of inflammatory cytokines, autophagy, and metabolism may identify novel therapeutic targets and improve the effectiveness of immunotherapy towards achieving the goal of precision oncology.
    Keywords:  IL-6/17; Immunometabolism; NSCLC; autophagy; inflammation; proteins; signaling pathways
    DOI:  https://doi.org/10.1080/08820139.2026.2698754
  36. Elife. 2026 07 08. pii: RP107745. [Epub ahead of print]14
    Depletion of extracellular asparagine impairs self-reactive T cells and ameliorates autoimmunity in a murine model of multiple sclerosis.
    Peter Georgiev, Sheila Johnson, Kiran Kurmi, Song-Hua Hu, SeongJun Han, Dillon Patterson, Thao H Nguyen, Linglin Huang, Dan Liang, Naomi Goldman, Thomas Conway, Hannah Creasey, Jared Rowe, Marcia C Haigis, Arlene H Sharpe.
      Amino acids play critical roles in the activation and function of lymphocytes. Here we show that the non-essential amino acid, asparagine, is essential for optimal activation and proliferation of CD4+ T cells. We demonstrate that asparagine depletion at different time points after CD4+ T cell activation reduces mitochondrial membrane potential and function. Furthermore, asparagine depletion at specific time points during CD4+ T cell differentiation reduces cytokine production in multiple CD4+ T cell subsets. In an adoptive transfer model of experimental autoimmune encephalomyelitis (EAE), myelin oligodendrocyte-specific pathogenic T helper 17 cells differentiated under Asn-deficient conditions exhibited reduced encephalitogenic potential and attenuated EAE severity. In a model of EAE induced by active immunization, therapeutic depletion of extracellular Asn significantly reduced disease severity. These results identify asparagine as a key metabolic regulator of the pathogenicity of autoreactive CD4+ T cells and suggest that targeting asparagine metabolism may be a novel therapeutic strategy for autoimmunity.
    Keywords:  autoimmune response/disease; immunology; inflammation; lymphocyte subsets; mouse
    DOI:  https://doi.org/10.7554/eLife.107745
  37. Adv Sci (Weinh). 2026 Jul 10. e23582
    Gut Microbiota, Immunity, and Metabolism in the Progression From Chronic Liver Disease to Hepatocellular Carcinoma.
    Yi Hu, Caiyan Lin, Lijie Zhang, Xue Jiang, Huawen Li, Yangzhe Wu.
      The progression from chronic liver injury to hepatocellular carcinoma (HCC) should be viewed as a heterogeneous continuum of immune, metabolic, fibrotic, and microbial remodeling rather than as a single linear route. Although this review uses the MASLD-MASH-fibrosis/cirrhosis-HCC sequence as a mechanistically informative model, the gut-liver-immune framework is also relevant, with important etiology-specific differences, to alcohol-associated liver disease (ALD), chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, and mixed-etiology liver disease. Across these contexts, hepatocyte lipotoxicity or viral/alcohol-induced injury, mitochondrial stress, endotoxemia, altered bile-acid signaling, fibrotic remodeling, and immune exhaustion progressively reshape the hepatic microenvironment toward tumor-permissive inflammation and immune escape. We integrate transcriptomic, single-cell, spatial, microbial, and metabolomic evidence to define stage- and etiology-dependent immunometabolic states. Particular emphasis is placed on microbial metabolites, including short-chain fatty acids, secondary bile acids, and tryptophan-derived indoles, which engage host receptors such as FFAR2/3, GPR109A, FXR, TGR5, AhR, and PXR to influence lipid metabolism, epithelial barrier integrity, cytokine programs, epigenetic remodeling, and antitumor surveillance. We further discuss how sex, baseline microbiome composition, hepatic zonation, and preclinical model selection influence disease trajectories and therapeutic responses. By focusing on the gut microbiota-metabolism-immunity axis, this review provides a systems-level framework for biomarker discovery, risk stratification, precision nutrition, and rational combination therapies. Targeting the coordinated interplay among diet, microbiota, metabolism, immunity, and the hepatic spatial niche may help intercept chronic liver disease before malignant transformation and improve therapeutic responses in established HCC.
    Keywords:  chronic liver disease; dietary interventions; gut microbiota; hepatocellular carcinoma; immunometabolism; microbial metabolites; precision nutrition
    DOI:  https://doi.org/10.1002/advs.202523582
  38. PLoS Pathog. 2026 Jul;22(7): e1014403
    Staphylococcus aureus rewires arginine metabolism to drive mammary aging via macrophage-epithelial crosstalk.
    Yuhang Jin, Kai Yang, Ruoxi Sun, Yu Cao, Dewei He, Junlong Bi, Wenjin Guo, Shoupeng Fu.
      As a common opportunistic pathogen, Staphylococcus aureus (S. aureus) can rapidly adapt to the host immune system and cause chronic infections. Currently, such chronic infections are extremely difficult to eliminate, severely impairing the function of tissues and organs. We observed localized tissue senescence in the mammary glands of mice with chronic S. aureus infection; however, the mechanism driving this senescence remains unclear. To address this, we employed a mouse model of chronic S. aureus-induced mastitis and an in vitro model of mouse mammary epithelial cells (mMECs) to confirm the inductive effect of S. aureus on tissue and cellular senescence. Through integrated analysis of the transcriptome and metabolome of mouse mammary tissues, it was found that the ornithine cycle was significantly disordered following S. aureus infection, wherein Arginase 1 (Arg1) serves as a key metabolic regulator. Notably, stimulation by S. aureus induces mammary epithelial cells to produce cytokines, thereby promoting the massive release of Arg1 by macrophages into the microenvironment, which constitutes one of the sources of abnormally elevated Arg1 in mammary tissue. This extracellular Arg1 is subsequently taken up by mammary epithelial cells, further accelerating the intracellular conversion of arginine to ornithine. The accumulation of ornithine and its downstream metabolites drives the occurrence of senescence in epithelial cells. Importantly, supplementation with excess arginine or ornithine can mimic this senescence phenotype, while knocking down Arg1 in epithelial cells can reverse this phenomenon. In summary, this study reveals a novel immunometabolic cross-regulation mechanism, specifically that Arg1 released by macrophages-triggered by mammary epithelial cells under S. aureus stimulation-acts as a paracrine senescence-inducing factor that acts back on mammary epithelial cells. The Arg1-ornithine axis holds promise as a potential therapeutic target for chronic infection-associated tissue senescence.
    DOI:  https://doi.org/10.1371/journal.ppat.1014403
  39. Res Sq. 2026 Jun 30. pii: rs.3.rs-10155437. [Epub ahead of print]
    Aging reprograms the functional, epigenetic, and metabolic landscape of macrophages.
    Manasa Suresh, Francisco Tapia Belmonte, Bryan T Weselman, Xintang Li, Marie Durr, Isabella Duchovny, Yanitza Gutierrez-Monsalve, Matias I Hepp, Satish Kumar R Noonepalle, Alexis Salas-Burgos, Alejandro Villagra.
      Immuno-senescence is a dominant risk factor of chronic diseases, yet the impact of aging on macrophages remain understudied, despite their involvement in age-related conditions. Here, we define macrophage aging by integrating transcriptomic, epigenetic, metabolic, and functional analyses across the lifespan. Besides aging hallmarks, we uncovered progressive changes in macrophages, including reduced responsiveness to both inflammatory and anti-inflammatory cues and an imbalanced cytokine and chemokine secretory profile. This age-driven remodeling is supported by significant rewiring of epigenetic regulators, particularly histone-modifying genes, alongside coordinated shifts in metabolism toward lipid activation and trafficking at the expense of mitochondrial redox programs. Strikingly, these alterations differ between M1- and M2-like macrophages, indicating phenotype-specific aging trajectories. Functionally, aged macrophages exhibit enhanced phagocytic capacity, diminished migratory ability, and preserved antigen presentation. Together, our findings establish that aging does not simply impair macrophages; it drives an active, multi-layered reprogramming process, providing a framework to address inflammaging and age-associated diseases.
    DOI:  https://doi.org/10.21203/rs.3.rs-10155437/v1
  40. Cell Metab. 2026 Jul 07. pii: S1550-4131(26)00189-0. [Epub ahead of print]38(7): 1264-1266
    Jack-of-a-new-trade: Itaconate targets the PPP/G6PD to control lung cancer.
    Stefanie K Wculek.
      Itaconate is known as an anti-inflammatory metabolite derived from macrophages that dampens immune responses; however, its role in cancer has emerged to be complex. Mansouri et al.1 report a previously unknown anti-cancer feature of (octyl-) itaconate as an inhibitor of glucose-6-phosphate dehydrogenase (G6PD) in the lung tumor microenvironment (TME) in macrophages and cancer cells.
    DOI:  https://doi.org/10.1016/j.cmet.2026.05.004
  41. Mater Today Bio. 2026 Aug;39 103426
    A metabolic amplification strategy for spherical nucleic acid immunogenicity driven by simvastatin-CpG codelivery.
    Lulu Zhang, Lin Yu, Jiaxi Zhu, Yuan Ding, Zheng Wang, Ruihong Yu, Lina Jiao, Zhimin Zhang, Yan Ma, Jinli Shi, Zhenguang Liu.
      Spherical nucleic acids (SNAs) are a promising platform for immunotherapy, although their limited innate immune activation may constrain therapeutic performance. Here, we report a simvastatin-CpG SNAs (S-SNAs) system that integrates a metabolic modulator with CpG to enhance immune activation. Mechanistically, simvastatin is found to potentiate CpG-induced innate immune signaling, likely through modulation of the mevalonate pathway, resulting in regulated macrophage activation in vitro. Integration into the SNAs architecture is associated with improved cellular uptake and enhanced RBD-specific humoral immune responses in vivo. In a murine melanoma model, the engineered S-SNAs exhibit antitumor activity and are associated with prolonged survival under the experimental conditions, without evident systemic toxicity. Overall, this work suggests that metabolic modulation may represent a useful strategy for improving the immunological performance of nucleic acid-based nanostructures.
    Keywords:  Cancer immunotherapy; Humoral immunity; Metabolic immune modulation; Mevalonate pathway; Spherical nucleic acids
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103426
  42. J Cell Biochem. 2026 Jul;127(7): e70104
    Tricarboxylic Acid (TCA) Cycle Enzyme Alpha-Ketoglutarate Dehydrogenase (KGDH) as a Nexus for the Regulation of Macrophage Polarization.
    Meijing Li, Ryan J Mailloux.
      Macrophage metabolism has been increasingly studied in recent years for its potential as a therapeutic target across multiple pathologies. In this article, we propose that the tricarboxylic acid (TCA) cycle enzyme alpha-ketoglutarate (KG) dehydrogenase (KGDH) serves as a nexus for regulating macrophage polarization toward pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes. This is achieved through modulation of mitochondrial hydrogen peroxide (mtH2O2) and the availability of the TCA cycle metabolites KG and succinate, which are important immunomodulatory molecules. We discuss the evidence showing KGDH is a potent source of mtH2O2 in various cell types and how it could use this reactive oxygen species (ROS) to modulate signaling pathways involved in macrophage differentiation. Coupled to this, we describe emerging evidence showing that KG and succinate exert opposite signaling effects in macrophages, with the former metabolite inducing an anti-inflammatory phenotype and the latter (succinate) promoting inflammation. This occurs through the regulation of dioxygenases involved in hypoxic signaling and epigenetic programming and the activation of G-protein coupled receptor 91 (GPR91) by succinate. Importantly, we contend that regulating KGDH influences the availability of these two metabolites, which, along with controlling mtH2O2 availability, helps control macrophage polarization. Collectively, increased mtH2O2 generation and succinate are known to induce a pro-inflammatory phenotype, whereas low mtH2O2 and high KG have the opposite effect. This suggests that KGDH is a key regulator of macrophage polarization by controlling the availabilities of these immunomodulatory metabolites.
    DOI:  https://doi.org/10.1002/jcb.70104
  43. PLoS Pathog. 2026 Jul 07. 22(7): e1014392
    Novel duck reovirus σC hijacks the mitochondrial COQ6-CoQ10 axis to drive NLRP3-dependent pyroptosis.
    Hui Yan, Lei Bei, Mingrui Zhao, Jiajun Wang, Pengxiang Jin, Chunmei Xu, Lin Ju, Yu Meng, Shijin Jiang, Ruihua Zhang.
      Mitochondrial metabolic homeostasis serves as a critical checkpoint that integrates cellular bioenergetics with innate immunity. While viruses often subvert mitochondrial functions to manipulate cell fate, the specific viral determinants that directly reprogram host metabolic enzymes to drive inflammatory injury remain incompletely defined. Here, using infection with a highly virulent novel duck reovirus (NDRV) strain as a model of systemic immunopathology, we identify the viral capsid protein σC as a metabolic virulence factor. We show that σC binds to the mitochondrial targeting sequence (MTS) of COQ6, a conserved monooxygenase required for coenzyme Q10 (CoQ10) biosynthesis, and blocks its mitochondrial import, thereby disrupting CoQ10 homeostasis. This metabolic blockade induces mitochondrial dysfunction, characterized by mtROS accumulation and the cytosolic release of oxidized mitochondrial DNA (ox-mtDNA). We demonstrate that ox-mtDNA acts as a danger signal that triggers NLRP3 activation and downstream gasdermin E (GSDME)-dependent pyroptosis. Moreover, σC knockdown in infected cells reduces ox-mtDNA release and attenuates pyroptosis. CoQ10 supplementation restores mitochondrial homeostasis and alleviates NDRV-induced inflammatory pathology in vitro and in vivo without detectably reducing viral RNA loads, consistent with a host-directed disease tolerance mechanism. Collectively, these findings define a σC-COQ6-CoQ10-ox-mtDNA-NLRP3 axis that links a structural avian orthoreovirus protein to metabolic reprogramming and highlight the COQ6-CoQ10 pathway as a tractable therapeutic target for limiting virus-induced inflammatory tissue damage.
    DOI:  https://doi.org/10.1371/journal.ppat.1014392
  44. ASN Neuro. 2026 ;18(1): 2696821
    Hijacking Sodium-Glucose Cotransporters: Fructose Drives Neuronal and Microglial Dysfunction.
    Salaheldeen Elsaid, Muhammad Asad Usmani, Xiangdong Wu, Junkai Hu, Nigus Ambaye, Sui Seng Tee.
      Excess fructose consumption has been implicated in metabolic disease, yet its impact on brain physiology and cellular metabolism remains poorly understood. The hippocampus expresses fructose transporters and fructolytic enzymes, suggesting potential vulnerability to fructose-induced metabolic stress. Here, we investigated fructose uptake mechanisms and downstream functional responses in BV2 microglia and HT22 hippocampal neurons using sodium manipulation, pharmacological inhibition, transporter expression profiling, and live-cell fluorescent sugar uptake assays. Hippocampal neurons exhibited strong sodium-sensitive, phlorizin-responsive fructose uptake, accompanied by reduced expression of facilitated hexose transporters and selective induction of Sglt1. In contrast, microglia demonstrated both sodium-sensitive and sodium-independent components of fructose uptake, associated with coordinated remodeling of GLUT and SGLT family members. Functionally, fructose exposure was associated with membrane hyperpolarization and reduced extracellular vesicle (EV) release in neurons, whereas microglia displayed membrane depolarization, enhanced EV secretion, and induction of pro-inflammatory genes. Knockdown of ketohexokinase (KHK) attenuated inflammatory gene expression and EV release in microglia, while pharmacological inhibition of sodium-dependent transport selectively reduced EV secretion. Complementary secondary analysis of hippocampal RNA-seq data from mice exposed to high-fat/high-fructose feeding revealed coordinated regulation of sodium-coupled transporters, ion channels, and synaptic gene programs, with partial normalization following SGLT inhibition. Together, these findings identify cell-type-specific fructose handling strategies in hippocampal neurons and microglia and suggest that sodium-dependent transport and fructolytic metabolism differentially influence membrane polarization, vesicle signaling, and inflammatory activation under metabolic stress.
    Keywords:  Fructose uptake; SGLTs; hippocampal neurons; microglia; neuroinflammation
    DOI:  https://doi.org/10.1080/17590914.2026.2696821
  45. Phytomedicine. 2026 Jun 29. pii: S0944-7113(26)00740-3. [Epub ahead of print]159 158509
    Liquiritigenin ameliorates adipocyte insulin resistance by inhibiting pro-inflammatory polarization of macrophages via regulation of the mtROS/OXPHOS axis.
    Cunqi Lv, Jie Tan, Huili Ouyang, Ziyang Zhang, Xi Liu, Wenya Zheng.
      Obesity-induced insulin resistance (IR) is closely associated with chronic inflammation and metabolic dysfunction in adipose tissue, in which macrophage polarization plays a pivotal role. Liquiritigenin (LQ), a natural flavonoid derived from licorice, exhibits potential metabolic regulatory effects; however, its role in high-fat diet (HFD)-induced obesity and insulin resistance, as well as the underlying mechanisms, remains unclear. In this study, an HFD-induced obese mouse model combined with multi-omics analyses and an in vitro co-culture system was employed to investigate the effects of LQ. LQ significantly improved glucose tolerance, insulin sensitivity, and lipid metabolism, and restored the expression of p-IRS1/IRS1, p-AKT/AKT, and GLUT4 in epididymal adipose tissue. Integrated analyses of network pharmacology, transcriptomics, and metabolomics revealed that LQ markedly reversed HFD-induced alterations in oxidative stress, mitochondrial dysfunction, and inflammatory pathways. Mechanistically, palmitic acid (PA) at physiologically relevant concentrations did not directly induce insulin resistance in adipocytes but instead promoted macrophage polarization toward the pro-inflammatory M1 phenotype, thereby impairing adipocyte insulin signaling. Further investigation showed that PA and HFD increased mitochondrial reactive oxygen species (mtROS), disrupted oxidative phosphorylation (OXPHOS), and induced mitochondrial dysfunction in macrophages, ultimately driving M1 polarization; these effects were markedly attenuated by the mtROS scavenger Mito-TEMPO. In contrast, LQ reduced mtROS levels, restored OXPHOS function, and maintained mitochondrial homeostasis, thereby suppressing pro-inflammatory macrophage polarization and improving insulin signaling and glucose uptake in adipocytes. Notably, these effects were more pronounced than those observed with dexamethasone under the same experimental conditions. These protective effects were abolished by the mtROS activator DMNQ. In conclusion, LQ alleviates adipose tissue insulin resistance by modulating macrophage polarization through the mtROS/OXPHOS axis, providing new mechanistic insights into immunometabolic regulation and supporting of applying LQ as a potential phytotherapy strategy for obesity-related metabolic disorders.
    Keywords:  Insulin resistance; Liquiritigenin; Macrophages; Mitochondrial reactive oxygen species; Obesity
    DOI:  https://doi.org/10.1016/j.phymed.2026.158509
  46. Nat Commun. 2026 Jul 08.
    Immune protection and persistence in Pseudomonas aeruginosa infections by pyruvate cross-feeding.
    Stefanos Lampadariou, Pablo Laborda, Lorenzo Masiero, Søren Molin, Helle Krogh Johansen, Ruggero La Rosa.
      Chronic infections by Pseudomonas aeruginosa in people with cystic fibrosis are characterized by persistent inflammation and oxidative stress, yet the mechanisms enabling bacterial persistence are not fully understood. Here, we identify a persistence mechanism mediated by pyruvate secretion resulting from mutations in the pyruvate dehydrogenase complex in clinical isolates of P. aeruginosa, with putative analogous mutations also identified in Staphylococcus aureus, Haemophilus influenzae and Stenotrophomonas maltophilia. These mutations lead to elevated extracellular pyruvate, which dampens host inflammatory responses and favors bacterial persistence. Pyruvate exerts multiple roles: scavenges reactive oxygen species such as H2O2, suppresses host immune activation both in airway epithelial cells and macrophages, and increases bacterial survival during phagocytosis. This metabolic crosstalk promotes bacterial persistence while reducing epithelial and macrophage inflammatory responses. Our findings reveal pyruvate as a bacterial immunometabolite that mimics host antioxidant defenses, reshaping the infection niche to favor long-term colonization. This work highlights the broader role of secreted metabolites in host-pathogen interactions and suggests new strategies targeting metabolic pathways to manage chronic infections.
    DOI:  https://doi.org/10.1038/s41467-026-75330-z
  47. Cell Rep. 2026 Jul 03. pii: S2211-1247(26)00721-7. [Epub ahead of print]45(7): 117643
    An IGF2BP3-dependent metabolic circuit governs macrophage recruitment and immunosuppression in glioblastoma.
    Weiwei Dai, Ruotong Tian, Ming Whye Chong, Jin Li, Bowen Yin, Zhuoyang Fan, Shasha Bian, Minfeng Shu.
      The glioblastoma microenvironment is highly immunosuppressive and enriched with macrophages, which critically promote tumor progression and confer resistance to current therapies. However, the molecular mechanisms by which glioblastoma cells orchestrate macrophage recruitment through post-transcriptional regulation remain poorly understood. Here, we identify a glioblastoma-intrinsic pathway whereby the m6A RNA modification reader IGF2BP3 couples RNA metabolism with metabolic competition and immune remodeling. Specifically, IGF2BP3 selectively binds and stabilizes m6A-modified transcripts encoding the methionine transporter SLC38A2, thereby enhancing methionine uptake by glioblastoma cells. This metabolic advantage creates a methionine-deprived state in neighboring macrophages, leading to reduced global m6A methylation and increased expression of the chemokine CCL5. Elevated CCL5 subsequently drives further macrophage infiltration, establishing a feedforward loop that amplifies nutrient competition and sustains immunosuppression within the tumor microenvironment. Together, our findings delineate an m6A-dependent metabolic circuit that governs macrophage recruitment in glioblastoma and suggest a therapeutic avenue to reprogram the tumor immune microenvironment.
    Keywords:  CCL5; CP: Cancer; IGF2BP3; SLC38A2; glioblastoma; methionine; tumor-associated macrophage
    DOI:  https://doi.org/10.1016/j.celrep.2026.117643
  48. J Leukoc Biol. 2026 Jul 03. pii: qiag085. [Epub ahead of print]118(7):
    Metabolic and epigenetic regulation of microglia memory in neurological disorders.
    Xiaoya Wang, Yunpeng Jia, Xinyi Yan, Youwei Wang.
      As tissue-resident innate immune cells of the central nervous system, microglia are capable of acquiring innate immune memory-a persistent state of functional reprogramming triggered by prior stimuli. This memory typically manifests as 3 distinct phenotypes: trained immunity, immune tolerance, and immune exhaustion. In this review, we synthesize current knowledge on the metabolic and epigenetic mechanisms that govern these 3 forms of microglial innate immune memory. We further summarize and discuss how each phenotype is induced in microglia and its respective pathophysiological roles in neurological disorders. Owing to their slow turnover and unique tissue-resident characteristics, microglia sustain long-lasting memory states that can profoundly influence the trajectory of neuroinflammation and neurodegeneration. Finally, we highlight the bidirectional effects of microglial immune memory on disease progression, discuss emerging therapeutic strategies aimed at modulating these memory states, and outline key translational challenges that remain to be addressed.
    Keywords:  epigenetic reprogramming; innate immune memory; microglia; neurodegenerative diseases; neuroinflammation
    DOI:  https://doi.org/10.1093/jleuko/qiag085
  49. Front Immunol. 2026 ;17 1743101
    The lactylation axis: bridging metabolic reprogramming and immunosuppression in the tumor microenvironment.
    Xingxing Tao, Yingjie Liu, Peishan Yu, Wenjiang Wu, Yanli Fu, Ping Lan, Shengzhu Jin.
      Protein lactylation, a novel post-translational modification (lysine lactylation, Kla) driven by the oncometabolite lactate, has emerged as a critical epigenetic mechanism that directly links cellular metabolic state to gene regulation. Within the tumor microenvironment (TME), lactate accumulation resulting from the Warburg effect provides abundant substrate for lactylation, positioning this modification as a central hub in cancer biology. This review systematically elucidates the dual role of lactylation in driving tumor progression. Intrinsically, lactylation promotes tumor cell malignancy by globally reshaping chromatin accessibility via histone modifications (e.g., H3K18la) and orchestrating oncogenic signaling pathways through non-histone protein modifications, thereby enhancing metabolic reprogramming, proliferation, invasion, and therapy resistance. Extrinsically, lactylation serves as a key immunosuppressive mechanism by reprogramming the function of immune cells within the TME. It drives macrophages toward an M2-like immunosuppressive phenotype, enhances the suppressive function of regulatory T cells (Tregs), and induces dysfunction and exhaustion in CD8+ T cells, collectively fostering an immune-privileged niche. We further discuss the promising therapeutic strategies targeting the lactylation axis, including inhibitors of lactate production or lactyltransferases, and their combination with immune checkpoint blockade, to reverse immunosuppression and overcome treatment resistance. In summary, understanding the lactylation axis establishes a novel metabolic-epigenetic-immune paradigm and suggests potential new frameworks for precision cancer therapy.
    Keywords:  cancer immunotherapy; epigenetics; immune evasion; metabolic reprogramming; protein lactylation; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1743101
  50. bioRxiv. 2026 Jun 29. pii: 2026.06.24.734305. [Epub ahead of print]
    Intestinal lipid metabolism controls immune response through NHR-68 and gut-brain signaling in C. elegans.
    Jie Ren, Yu Sang, Young-Mo Kim, Ernesto S Nakayasu, Alejandro Aballay.
      Animals must allocate limited energetic resources across competing defense programs in response to infection. Here, we show that the conserved nuclear hormone receptor NHR-68 integrates fatty acid metabolism with the neural control of molecular and behavioral immunity in Caenorhabditis elegans . Acting in parallel with NHR-10, NHR-68 controls genes involved in polyunsaturated fatty acid (PUFA) metabolism. Loss of NHR-68 disrupts linoleic acid (LA) homeostasis, impairing pathogen avoidance behavior. Supplementation with LA restores avoidance, and fat-3 inhibition, which elevates LA, enhances pathogen avoidance, whereas loss of LA synthesis by fat-2 inhibition diminishes this behavior, indicating that LA promotes behavioral immunity. We further show that NHR-68 acts in the intestine to regulate linoleic acid homeostasis, and that changes in intestinal lipid metabolism influence an AWC-dependent pathogen-avoidance circuit through intestine-to-neuron communication. NHR-68 suppresses activation of the PMK-1/p38 MAPK and DAF-16/FOXO pathways, which mediate molecular immune responses. These findings identify a gut-brain transcriptional circuit that connects intestinal lipid metabolism to neural and immune outputs, revealing a mechanism by which the metabolic state coordinates behavioral and molecular defenses to optimize host protection.
    DOI:  https://doi.org/10.64898/2026.06.24.734305
  51. PLoS Pathog. 2026 Jul;22(7): e1014335
    Japanese encephalitis virus hijacks the host purine biosynthetic network to promote viral replication in neurons.
    Jun Gu, Chencheng Fan, Shengxian Xiang, Ling'en Yang, Jia Liu, Youhui Si, Bibo Zhu, Yingjie Sun, Chan Ding, Shengbo Cao, Jing Ye.
      Japanese encephalitis virus (JEV) is an important neurotropic orthoflavivirus that poses a threat to both human and animal health. However, the mechanism underlying its rapid replication in the central nervous system (CNS) remains poorly understood. In this study, we conducted metabolomic profiling of JEV-infected mouse brains and neurons, revealing a profound reprogramming of central carbon metabolism, particularly an enhancement in nucleotide synthesis. Integrated multi-omics analyses confirmed that JEV infection transcriptionally upregulates key enzymes involved in de novo purine biosynthesis (DNPB), one-carbon (1C) metabolism, and the pentose phosphate pathway (PPP) in neurons. Pharmacological inhibition of the core DNPB enzymes potently suppressed JEV replication in neurons and reduced both viral loads and neuroinflammation in JEV-infected mice, suggesting the essential role of DNPB in JEV replication within CNS. Mechanistically, we delineated the critical functions of both the non-oxidative PPP and MTHFD2-mediated 1C metabolism, which jointly supply essential precursors, such as ribose-5-phosphate and formyl groups, for the de novo biosynthesis of purines required for viral RNA replication. These findings unveil a strategy by which JEV co-opts the host's purine biosynthetic machinery to fulfill the nucleotide demands for its genomic replication, establishing DNPB and its supporting pathways as promising therapeutic targets for infections caused by JEV and other neurotropic viruses.
    DOI:  https://doi.org/10.1371/journal.ppat.1014335
  52. Biochim Biophys Acta Gen Subj. 2026 Jul 10. pii: S0304-4165(26)00078-4. [Epub ahead of print] 130978
    ETV4 enhances glycolysis to suppress NK-cell cytotoxicity in the immune microenvironment of colon cancer.
    Zixing Zhang, Pengfei Wang, Yingchuan Chen, Jian Wang, Weifeng Yang, Wenquan Ou, Xing Huang, Yao Wei, Xinwei Zhao, Xiaohua Wu.
      Immune evasion in colon cancer (CC) is largely driven by the functional suppression of NK cells, yet the specific regulatory role of ETV4 in this process remains poorly defined. We first analyzed ETV4 expression levels in CC through bioinformatics prediction and qPCR validation. A tumor-NK cell co-culture system was established to assess NK cell cytotoxicity and glycolytic metabolic profiles, which were examined via Seahorse and lactate/glucose assays. A nude mouse xenograft model combined with the glycolysis inhibitor 2-DG was applied for validation. ETV4 was significantly upregulated in CC tissues, and its high expression correlated with adverse clinical prognosis and decreased intratumoral NK cell infiltration. ETV4 potentiated tumor glycolysis by upregulating the expression of key glycolytic enzymes LDHA and PDK1, which consequently impairs NK cell cytotoxicity and the production of NK cell effector molecules. Glycolysis inhibition reversed this NK-cell suppression. ChIP-qPCR and dual-luciferase reporter assays validated that ETV4 transcriptionally activated LDHA. In vivo, ETV4 accelerated tumor growth via glycolysis, and this effect was blocked by 2-DG treatment. In conclusion, by transcriptionally activating LDHA, ETV4 facilitates glycolysis and thereby inhibits NK cell-mediated antitumor immunity in CC The ETV4-glycolysis axis may serve as a therapeutic target.
    Keywords:  Colon cancer; ETV4; Glycolysis; NK cells
    DOI:  https://doi.org/10.1016/j.bbagen.2026.130978
  53. Front Endocrinol (Lausanne). 2026 ;17 1814026
    Sex specific pattern of adipose expansion, inflammation and dysfunction with short term high fat diet exposure.
    Julia Skibniewska, Symmarana Desai, Lucy Casell-Kelley, Jessica Maung, Abhimanyu Sastry, Janie McMillin, Heather Day, Kanakadurga Singer, Mita Varghese.
       Background: While body mass index (BMI) and weight gain are commonly used indicators of metabolic disease risk, intrinsic features of adipose tissue function such as adipocyte hypertrophy and inflammation may serve as earlier and more accurate predictors of metabolic dysfunction. Sex specific responses in adipose function may lead to sex differences in how adiposity associates with metabolic disease.
    Objective: This study aimed to determine the early sequence of events leading to adipose tissue dysfunction and metabolic inflammation in response to a high-fat diet (HFD), with a focus on sex-specific differences in adipose and immune responses during short-term high fat dietary exposure.
    Methods: Male and female C57BL/6J mice were fed either a normal chow diet or HFD (60% fat) for 1, 2, 4, 6 weeks, or for 16 weeks, starting at 6 weeks of age. Adipose tissue mass, adipocyte size, glucose and insulin levels, inflammatory gene expression, and adipose tissue macrophage (ATM) populations were measured using immunohistochemistry, flow cytometry, gene expression, and metabolic assays. Serum and GWAT explant media proteomic evaluations were conducted using the Olink platform.
    Results: HFD induced rapid adipose expansion in both sexes, but male mice exhibited greater weight gain, adipocyte hypertrophy, and insulin resistance over time. Males also demonstrated an earlier and more pronounced accumulation of pro-inflammatory CD11c+ ATMs in gonadal adipose tissue, alongside increased inflammatory gene expression and inflammatory chemokines and cytokines. Female mice exhibited a delayed and less robust inflammatory response. Notably, metabolic dysfunction, including hyperinsulinemia, preceded inflammation, particularly in males.
    Conclusion: Short term HFD induces sex-specific adipose tissue remodeling and metabolic dysfunction, with males showing earlier onset of both adipocyte hypertrophy and inflammation. These findings highlight the importance of sex as a biological variable in early metabolic disease development and suggest that insulin resistance may precede inflammation, which precedes metabolic dysfunction in the pathogenesis of adipose dysfunction.
    Keywords:  Olink; adipose; inflammation; insulin resisitance; sex differences
    DOI:  https://doi.org/10.3389/fendo.2026.1814026
  54. Mucosal Immunol. 2026 Jul 04. pii: S1933-0219(26)00079-6. [Epub ahead of print] 100377
    Mucin degradation by Akkermansia muciniphila promotes Alistipes-dependent tryptophan metabolism and Th17-driven autoimmunity.
    Xun Lin, Ankita Singh, Xindi Shan, Suzanne Tawch, Isabel Sakarin, Tej Bahadur, Nancy McLinskey, Patricia Melville, Bettina C Fries, Patricia K Coyle, James Collins, Andriy Morgun, Natalia Shulzhenko, Jessica Seeliger, Timothy W Hand, Lijun Xia, Olga Syritsyna, Pawan Kumar.
      Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system associated with alterations in gut commensals, including Akkermansia muciniphila (A. muciniphila). However, its role in MS remains unclear. Here, we report elevated serum lipopolysaccharide (LPS) and anti-LPS IgG levels in patients with relapsing-remitting MS (RRMS), indicating compromised gut barrier integrity. Notably, RRMS patients also exhibited increased serum anti-A. muciniphila IgA and enhanced A. muciniphila-induced Th17 responses in peripheral blood mononuclear cells (PBMCs). Using experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, we found that A. muciniphila colonization worsened EAE severity, with increased infiltration of GM-CSF+CD4+ and IL-17A+CD4+ T cells in spinal cord. Mechanistically, A. muciniphila colonization enhanced tryptophan metabolism and elevated levels of aryl hydrocarbon receptor (AhR) agonists, including indole derivatives, during EAE. Although A. muciniphila does not directly metabolize tryptophan, it promotes expansion of tryptophan-utilizing bacterium Alistipes onderdonkii (A. onderdonkii) through mucin degradation. We further demonstrate that A. onderdonkii utilizes mucin-derived metabolites, including galactose and N-acetylneuraminic acid (NANA). Importantly, dietary tryptophan restriction significantly attenuated EAE severity. Collectively, these findings reveal a cross-feeding mechanism in which A. muciniphila supports growth of A. onderdonkii, thereby enhancing microbial tryptophan metabolism and production of AhR agonists that drive Th17-mediated neuroinflammation.
    Keywords:  Akkermansia muciniphila; EAE; Th17 cells
    DOI:  https://doi.org/10.1016/j.mucimm.2026.100377
  55. Sci Immunol. 2026 Jul 10. 11(121): eaeb5857
    Sp1 links CD46 to CD4 T cell metabolic fitness, survival, and retroviral control.
    Parul Singh, Luopin Wang, Pavitra Ramdas, Shyaman M Jayasundara, Gaelle Le Friec, Natalia Kunz, Prakriti Mudvari, Erin E West, Ayden Case, Nicolas S Merle, Jack A Bibby, Henrik Hasle, Eli A Boritz, Majid Kazemian, Claudia Kemper.
      CD46, a human-specific complement receptor, regulates gene programs essential for T helper 1 (TH1) cell differentiation, yet how it exerts direct transcriptional control remains unclear. We show that the CD46 signaling domain cytoplasmic tail 1 (CYT-1) engages the transcription factor Sp1 in human CD4 T cells to dynamically modulate Sp1-DNA interactions. Beyond promoting TH1 cell induction, CD46-Sp1-controlled programs support naive CD4 T cell survival by maintaining nutrient transporter expression and suppressing the intrinsic caspase 9-caspase 3 apoptotic pathway. The CD46-Sp1 axis also restrains HIV transcription in infected CD4 T cells in vitro. Disruption of CYT-1-Sp1-regulated programs identifies T cells from individuals with HIV who exhibit incomplete viral suppression during antiretroviral therapy. Together, these findings define a human-specific transcriptional mechanism linking complement signaling to metabolic adaptation, apoptosis regulation, and antiviral defense, highlighting an unexpected role for CD46 in coordinating T cell homeostasis and host protection.
    DOI:  https://doi.org/10.1126/sciimmunol.aeb5857
  56. Front Immunol. 2026 ;17 1865859
    Metabolic regulation and immunosuppressive functions of lipid-associated macrophages in pancreatic ductal adenocarcinoma.
    Tongyuan Zhang, Mingze Zhang, Xiaoqin He, Yuefeng Zhang.
       Introduction: Pancreatic ductal adenocarcinoma (PDAC) exhibits a profoundly immunosuppressive tumor microenvironment, with tumor-associated macrophages (TAMs) being the most abundant immune infiltrate. Among them, lipid-associated macrophages (LAMs) have emerged as a distinct subpopulation driving immune evasion through metabolic reprogramming.
    Methods: We conducted a narrative review by systematically searching PubMed, Web of Science, and Scopus for articles on LAMs in PDAC up to December 2023. Key themes were synthesized to cover defining markers, metabolic pathways, immunosuppressive functions, and therapeutic strategies.
    Results: LAMs are characterized by co-expression of TREM2, APOE, CD9, and lipid-handling genes, and their accumulation correlates with poor prognosis. They undergo metabolic rewiring involving CD36-mediated lipid uptake, dysregulated cholesterol efflux, fatty acid oxidation, and de novo lipogenesis, which collectively enforce an immunosuppressive phenotype. LAMs interact bidirectionally with cancer-associated fibroblasts and directly suppress CD8+ T cells and NK cells. Preclinical targeting of CD36, TREM2, or FAO shows promise but faces challenges in toxicity and delivery.
    Discussion: LAMs represent a potential therapeutic vulnerability in PDAC, but the field is still in its early stages. Future work should focus on establishing causal evidence in PDAC-specific models, developing tumor-selective delivery systems, and validating biomarkers for patient stratification.
    Keywords:  immunosuppression; lipid metabolism; lipid-associated macrophages; pancreatic ductal adenocarcinoma; tumor immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1865859
  57. Front Immunol. 2026 ;17 1882514
    Macrophage-mediated nutrient recycling: evolutionary insights into the metabolic role of professional phagocytes.
    Gabriela Krejčová, Adam Bajgar.
      Removal of senescent and damaged cells is fundamental for tissue homeostasis. While macrophage recognition and clearance of apoptotic cells are well characterized, the ultimate fate of the digested material remains poorly understood. Here, we explore current knowledge on the fate of engulfed material and examine how the metabolic nature of engulfed cargo shapes downstream signaling and phagocyte polarization. We also discuss emerging evidence that macrophages act as metabolic hubs, recycling and supplying nutrients to surrounding tissues. Drawing on studies in invertebrate phagocytes, we explore the evolutionary origins of this "nurturing" function and highlight its conservation in mammals, emphasizing its physiological relevance and potential contributions to metabolic disease.
    Keywords:  coelomocytes; efferotabolism; hemocytes; innate immunity; macrophages; nutrient recycling; nutritive phagocytosis; phagocytes
    DOI:  https://doi.org/10.3389/fimmu.2026.1882514
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