bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–08–09
43 papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Glucose metabolism in tumor-associated macrophage plasticity and cancer immunity.
  2. Macrophage metabolic reprogramming: A central hub linking multicellular crosstalk to organ vulnerability in sepsis.
  3. Metabolic Profiling of Circulating and Tumour-Infiltrating T Cells Uncovers Bioenergetic Checkpoints Linked With Immune and Clinical Skewing in Melanoma Patients.
  4. Lactylation at the crossroads of metabolism and immunity in renal injury and transplant rejection.
  5. Mitochondrial reactive oxygen species regulate HIF-1α stabilization and methylglyoxal accumulation in classically activated mouse macrophages.
  6. Metabolic reprogramming orchestrates microglial fate in cerebral ischemia-reperfusion injury: a spatiotemporal immunometabolic perspective.
  7. Metabolic-epigenetic crosstalk in innate immune cell plasticity within the tumor microenvironment.
  8. When reoxygenation fails: a dynamical model of HIF-1 α -mediated metabolic breakdown under hypoxia and SARS-CoV-2 infection.
  9. MCT4-mediated lactate efflux promotes STING-dependent dendritic cell antitumor immunity.
  10. Meta-inflammation through the lens of macrophage programming and nutrient-sensing ghrelin signaling.
  11. The Pentose Phosphate Pathway in Immunotherapy.
  12. Enforcing mTORC1 activity in therapeutic CD4+ T cells promotes persistence but eventual immune exhaustion.
  13. Stress Hyperglycemia Drives CD4+ T Cell PANoptosis and Postoperative Organ Injury via Monocyte-Derived Succinate.
  14. Mitochondrial transfer in the tumor microenvironment: mechanisms, immunometabolic consequences, and therapeutic implications.
  15. Lactate facilitates largemouth bass virus replication by promoting cholesterol biosynthesis.
  16. Editorial: Metabolite-induced metabolic reprogramming in the immune system.
  17. Virus-induced deconjugation of ISG15 dysregulates innate immunity and cellular metabolism.
  18. Fetal sex shapes maternal immune adaptation: placental extracellular vesicles differentially reprogram the phenotype, metabolism, and function of circulating monocytes.
  19. HPV-driven metabolic reprogramming promotes T cell exhaustion: targeting immunometabolic barriers with natural products.
  20. Metabolic rewiring of the dendritic cell-T cell axis: tumour-derived barriers and therapeutic opportunities.
  21. Reframing macrophage polarization through cholesterol efflux: an organelle-coupled immunometabolic model.
  22. Context-dependent lysophosphatidic acid signalling in inflammation: evidence hierarchy, myeloid regulation and translational gaps.
  23. Metabolic exhaustion and immune ageing in rheumatoid arthritis.
  24. Inflammation as a pleiotropic regulator of megakaryocyte and platelet hemostatic, immune, and metabolic function.
  25. Integrating T cell signaling and metabolism to enhance T cell engager responses in solid tumors.
  26. Epigenetic and metabolic reprogramming of innate immune cells establishes immunological memory in the Schistosomiasis vector snail Biomphalaria glabrata.
  27. Lactate promotes macrophage-derived foam cell formation and atherosclerosis.
  28. PGK1-driven histone lactylation fuels MDSC-driven immune evasion and tumor progression in triple-negative breast cancer.
  29. Distinct immunometabolic signatures in peripheral blood mononuclear cells are linked to systemic inflammation in type 2 diabetes and diabetic kidney disease.
  30. Arginine downstream metabolites spermidine and putrescine, but not spermine, contribute to PCV2 replication.
  31. Pyruvate kinase M2 is elevated in systemic sclerosis and plays a role in its pathogenesis.
  32. Sarcopenia and sepsis fuel a self-perpetuating cycle of immunometabolism decline.
  33. Macrophage-to-myofibroblast transition-derived itaconate promotes bone metastasis in lung cancer through targeting of HSPA8.
  34. Fatty acid amide metabolism in systemic lupus erythematosus: Evidence, mechanisms, and translational potential.
  35. Metabolic control of RNA methylation in rheumatoid arthritis: from synovial stress to pathogenic cellular adaptation.
  36. A bacterial fatty acid enzyme hijacks nucleic acid-sensing Toll-like receptor signaling.
  37. RSAD2/VIPERIN and CMPK2 coordinate an immunometabolic response to Epstein-Barr Virus.
  38. Sodium Butyrate Attenuates Renal Fibrosis by Regulating Glycolysis and Histone H4K12 Lactylation in Diabetic Kidney Disease.
  39. Febrile-range temperature selectively limits sustained pDC-Derived IFN-α via attenuation of STAT1-Dependent feedback signaling.
  40. Targeting IMPDH2 by Casticin attenuates psoriatic inflammation by suppressing STAT3 activation in keratinocytes.
  41. Gq Signaling in Microglia Triggers Interferon Responses and Improves Outcome After Ischemic Stroke.
  42. Host inflammation-derived citrate enhances Salmonella Typhimurium pathogenesis by fueling growth and activating virulence.
  43. Fangchinoline drives NOS2-dependent host immunity to restrict intracellular enteric pathogens.
  1. Front Cell Dev Biol. 2026 ;14 1885974
    Glucose metabolism in tumor-associated macrophage plasticity and cancer immunity.
    Bang Liu, Jin Wang, Xiulin Jiang, Xiangyu Chen.
      Tumor-associated macrophages (TAMs) are key immune cells in the tumor microenvironment and play critical roles in tumor progression, immune escape, and therapeutic response. Their functional plasticity is closely regulated by metabolic reprogramming, particularly glucose metabolism. Glucose-related pathways, including glycolysis, gluconeogenesis, the pentose phosphate pathway, glycogen metabolism, and pyruvate/lactate metabolism, influence TAM polarization, cytokine production, phagocytosis, antigen presentation, and T cell interactions. In many tumors, enhanced glycolysis and lactate accumulation promote M2-like TAM polarization and suppress CD8+ T cell activity, whereas certain metabolic programs may support M1-like anti-tumor functions under specific conditions. This mini review summarizes major glucose metabolic pathways involved in TAM regulation, highlights their context-dependent pro- and anti-tumor roles, and discusses therapeutic strategies for reprogramming TAM metabolism to improve anti-tumor immunity and immunotherapy response.
    Keywords:  HIF-1α; glucose metabolism; glycolysis; immunometabolism; lactate; metabolic reprogramming; pentose phosphate pathway (PPP); pyruvate metabolism
    DOI:  https://doi.org/10.3389/fcell.2026.1885974
  2. Tissue Cell. 2026 Jul 29. pii: S0040-8166(26)00525-2. [Epub ahead of print]104(Pt 1): 103831
    Macrophage metabolic reprogramming: A central hub linking multicellular crosstalk to organ vulnerability in sepsis.
    Bushi Zhang, Huali Zhang, Liqin Cheng, Nian Wang.
      Sepsis is a life-threatening syndrome characterized by dysregulated host responses to infection, often progressing to multiple organ dysfunction syndrome (MODS). Recent evidence highlights macrophage metabolic reprogramming as a critical driver of immune responses, yet macrophages operate within a broader immunometabolic network involving dendritic cells, neutrophils, and lymphocytes that collectively shape sepsis outcomes. The coordination of these metabolic changes across multicellular interactions and their contribution to organ-specific vulnerability remain poorly understood. Here we present a holistic framework linking macrophage metabolism to multicellular communication and organ vulnerability. We discuss how glycolysis, amino acid metabolism, and fatty acid oxidation alter macrophage states via epigenetic and signaling mechanisms, producing metabolites that connect metabolism to inflammation. These signals reshape cellular networks through cytokines, extracellular vesicles, and damage-associated molecule patterns (DAMPs), differentially impacting organs with diverse metabolic demands, including the heart, lung, liver, kidney, brain, and intestine, resulting in distinct injury patterns. Our framework enhances understanding of sepsis-induced organ heterogeneity and advocates for stage-specific, organ-targeted therapies that consider integrated multicellular immunometabolic contributions.
    Keywords:  Immunometabolism; Macrophage; Metabolic reprogramming; Organ vulnerability; Sepsis
    DOI:  https://doi.org/10.1016/j.tice.2026.103831
  3. Immunology. 2026 Aug 04.
    Metabolic Profiling of Circulating and Tumour-Infiltrating T Cells Uncovers Bioenergetic Checkpoints Linked With Immune and Clinical Skewing in Melanoma Patients.
    Hugo Brouque, Kareem Mahdy, Stephane Mouret, Sylvain Henry, Camille Niveau, Mélanie Cettour-Cave, Martin Pelosse, Florence de Fraipont, Julie Charles, Andrei Turtoi, Philippe Saas, Caroline Aspord.
      Metabolism is critical for immune cell functions. Tumours shape their microenvironment to render it metabolically hostile for infiltrating immune cells. While targeting immunometabolism emerges as a promising way to reinvigorate anticancer immunity, a deeper understanding of the metabolic disturbances of immune cells is needed. Here, we explored how the metabolic status of T cells governs immune skewing from circulating and tumour-infiltrating CD4+ and CD8+ T cells of melanoma patients at a single-cell level using the SCENITH method and targeted metabolomics. Circulating and tumour-infiltrating T cells from patients displayed a decreased mitochondrial dependency associated with an enhanced glycolytic capacity and a skewed metabolic reprogramming upon stimulation. Such metabolic disturbances were linked to the activation status, immune checkpoint profile and functional orientation of T cells, underlining critical connections between T-cell features and metabolic patterns. Targeted metabolomics within sorted CD4+/CD8+ T cells identified a decrease in citrulline, cysteine and threonine within all subsets in patients, together with a sharp rise in sterol cholesterol CE(20:2) and ceramide dhCer(d18:0/22:0) within tumour-infiltrating CD4+ T cells, and in glycerolipid DG(16:0/16:0) within CD8+ T cells in blood and tumour. We further outlined a metabolic-checkpoint-based signature composed of six genes coding enzymes/transporters connected to the imbalanced metabolites found within tumour-infiltrating T cells (LIPA, DGKA, GLUL, SLC38A1, SLC7A7, GCH1) that shape patients' clinical outcome. These findings outline the skewed bioenergetic profiles of T cells and depict metabolic checkpoints associated with immune subversion. Harnessing metabolic pathways is promising for developing innovative therapies to restore optimal anti-tumour responses and improve clinical success.
    Keywords:  SCENITH; T cells; immunometabolism; melanoma; metabolomics
    DOI:  https://doi.org/10.1111/imm.70185
  4. Int Immunopharmacol. 2026 Aug 05. pii: S1567-5769(26)01080-5. [Epub ahead of print]187 117234
    Lactylation at the crossroads of metabolism and immunity in renal injury and transplant rejection.
    Boyang Yu, Yufeng Zhao, Jiaheng Wu, Yirui Cao, Siyue Chen, Yichen Jia, Tongyu Zhu, Dong Zhu.
      Lactate, once regarded merely as a metabolic waste product of glycolysis, has recently emerged as a potent signaling molecule and regulator of cellular function. The discovery of protein lactylation, a novel post-translational modification derived from lactate metabolism, has revealed a critical mechanism linking metabolic activity with epigenetic and functional reprogramming of cells. Both histone and non-histone lactylation serve as integrators of glycolytic flux, modulating gene expression, enzyme activity, and immune responses in diverse physiological and pathological contexts. The immune system is particularly sensitive to these metabolic cues. Accumulation of lactate in hypoxic or inflamed tissues reprograms macrophages, neutrophils, NK cells, and T cells through lactylation, shaping their activation, polarization, and effector functions. In the kidney, which is highly vulnerable to hypoxia and metabolic stress, lactate-driven immune reprogramming has profound consequences. Acute insults such as ischemia-reperfusion injury (IRI) and acute rejection (AR) in transplantation are characterized by glycolytic metabolic reprogramming and lactate accumulation, which in turn influence immune and parenchymal cell behavior. Thus, understanding the role of lactylation and lactic acid-induced immune cell malfunction in renal pathophysiology provides not only mechanistic insight but also potential therapeutic targets for acute kidney injury, chronic kidney disease, and transplant rejection.
    Keywords:  Immunity; Kidney diseases; Lactylation
    DOI:  https://doi.org/10.1016/j.intimp.2026.117234
  5. Immunometabolism (Cobham). 2026 Jul;8(3): e00085
    Mitochondrial reactive oxygen species regulate HIF-1α stabilization and methylglyoxal accumulation in classically activated mouse macrophages.
    Daniel Prantner, Mark A Watson, Martin D Brand, Jules C Paton, Stefanie N Vogel.
       Background: The economic and medical burden of sepsis worldwide underscores the need for novel therapeutics. Early sepsis involves dramatic metabolic changes. Classically activated macrophages, stimulated with lipopolysaccharide and interferon-γ, shift their metabolism to glycolysis. The reactive glycolytic metabolite, methylglyoxal, accumulates and has been associated with adverse outcomes in sepsis. We previously demonstrated that hypoxia-inducing factor-1α (HIF-1α) contributes to methylglyoxal accumulation. Treatment with lipopolysaccharide or interferon-γ individually stabilized HIF-1α protein; however, co-stimulation with both lipopolysaccharide and interferon-γ accelerated HIF-1α stabilization, implying a shared upstream mediator. Therefore, we sought to characterize mechanisms underlying methylglyoxal accumulation.
    Methods: Quantitative polymerase chain reaction and immunoblotting were used to analyze HIF-1α expression in classically activated primary mouse macrophages.
    Results: Nos2 expression was induced by lipopolysaccharide or interferon-γ and markedly enhanced by combined treatment, possibly linking inducible nitric oxide synthase (iNOS) activity to HIF-1α stabilization. Inhibiting iNOS with l-NG-Nitro arginine methyl ester (l-NAME) reduced HIF-1α stabilization in a dose-dependent manner. Mitochondrial reactive oxygen species (mROS), generated following nitric oxide inhibition of cytochrome oxidase, similarly contributed to HIF-1α stabilization, as shown by the effects of suppressors of ROS production by mitochondrial complex I (S1QEL1.1) and III (S3QEL1.2) and the compartment-specific antioxidant Mito-TEMPO. Blocking mROS also decreased Il1b, Il6, and Cxcl10 expression in activated macrophages, supporting a broader impact on inflammation. Additionally, S1QEL1.1 treatment reduced accumulation of methylglyoxal.
    Conclusions: These data support a model in which nitric oxide-mediated mitochondrial dysfunction increases mROS, promoting HIF-1α stabilization and methylglyoxal accumulation, thereby shaping macrophage inflammatory responses. Thus, targeting mROS may offer a therapeutic strategy to improve sepsis outcomes.
    Keywords:  electron transport; glycation; hypoxia-inducible factor; inflammation; innate immunity macrophage; mitochondrial respiratory chain complex; nitric oxide synthase
    DOI:  https://doi.org/10.1097/IN9.0000000000000085
  6. Front Immunol. 2026 ;17 1831494
    Metabolic reprogramming orchestrates microglial fate in cerebral ischemia-reperfusion injury: a spatiotemporal immunometabolic perspective.
    Meng Zhang, Huimin Li, Wei Zhang.
      Cerebral ischemia-reperfusion injury (CIRI) represents a critical pathological cascade that paradoxically exacerbates neurological damage following revascularization therapy for acute ischemic stroke (AIS). The pathogenesis of CIRI is intricately linked to dysregulated neuroinflammation, with microglia-the resident innate immune cells of the central nervous system-serving as central orchestrators of this response. Emerging evidence indicates that microglia undergo profound metabolic reprogramming encompassing glucose metabolism, the tricarboxylic acid (TCA) cycle, fatty acid metabolism, and NAD+ homeostasis, which fundamentally dictates their functional polarization and consequent neuroinflammatory outcomes. Rather than existing as discrete pro-inflammatory versus reparative phenotypes (classically referred to as M1/M2), microglia exhibit a continuum of activation states with distinct metabolic signatures that evolve dynamically across spatiotemporal dimensions following CIRI. Here, we systematically synthesize current knowledge on the core molecular mechanisms underlying microglial metabolic reprogramming, including the ACOD1/itaconate pathway, the glycolysis-OxPhos balance, and NAMPT-mediated NAD+ homeostasis. We critically examine the intricate crosstalk between these metabolic pathways and neuroinflammatory signaling cascades, revealing how metabolic checkpoints serve as integrative nodes that decode microenvironmental cues into functional outputs. Building on this mechanistic foundation, we evaluate emerging intervention strategies targeting metabolic reprogramming, stratified by intervention modality and translational readiness, with emphasis on agents in active clinical development. Finally, we identify prevailing challenges-including spatiotemporal heterogeneity, cell-specific targeting requirements, and clinical translation barriers-and outline future directions integrating single-cell omics, systems biology approaches, and advanced delivery systems. This comprehensive analysis aims to provide a refined conceptual framework and highlight promising therapeutic avenues for mitigating CIRI through strategic modulation of microglial immunometabolism.
    Keywords:  cerebral ischemia-reperfusion injury; immunometabolism; metabolic reprogramming; microglia; neuroinflammation; redox signaling
    DOI:  https://doi.org/10.3389/fimmu.2026.1831494
  7. Exp Mol Med. 2026 Aug 06.
    Metabolic-epigenetic crosstalk in innate immune cell plasticity within the tumor microenvironment.
    Junho Noh, Jaehyun Lee, Chaelin You, Kyuho Kang.
      The tumor microenvironment exerts profound metabolic and epigenetic pressures that shape the plasticity of innate immune cells, influencing their capacity to promote or suppress tumor progression. Emerging evidence highlights the intricate interplay between metabolic reprogramming and epigenetic modifications in macrophages, neutrophils, and other innate immune populations within the tumor microenvironment. Tumor-derived metabolites, hypoxia, and nutrient availability dynamically regulate chromatin accessibility, histone modifications, and DNA methylation patterns, thereby driving context-dependent immune phenotypes. Notably, metabolic rewiring can imprint long-lasting epigenetic changes, a phenomenon known as innate immune memory, which alters subsequent immune responses. Here, we discuss how key metabolic pathways, including glycolysis, fatty acid oxidation, and amino acid metabolism, govern innate immune cell fate and function via epigenetic mechanisms. We also highlight recent advances in epigenomic profiling that have unveiled distinct chromatin landscapes associated with innate immune dysfunction across cancer types. Finally, we explore emerging therapeutic strategies that target the metabolic-epigenetic axis to restore innate immune surveillance and enhance immunotherapy efficacy. A deeper understanding of this metabolic-epigenetic crosstalk could reveal novel avenues for modulating innate immunity in cancer therapy.
    DOI:  https://doi.org/10.1038/s12276-026-01802-3
  8. J Math Biol. 2026 Aug 06. pii: 34. [Epub ahead of print]93(3):
    When reoxygenation fails: a dynamical model of HIF-1 α -mediated metabolic breakdown under hypoxia and SARS-CoV-2 infection.
    Alexander Ryvkin, Yuri Kogan.
      Cells normally combine glycolysis and oxidative phosphorylation (OXPHOS) to meet energy demands, but this balance shifts under pathological conditions. During SARS-CoV-2 infection, hypoxia, viral entry, and elevated tissue lactate alter cellular metabolism. To explore these effects, we propose a parsimonious mathematical model describing how oxygen levels, viral infiltration, and extracellular lactate jointly regulate metabolic balance through HIF-1 α protein, inside the cell, accounting for lactate's biphasic, non-monotonic influence on glycolysis. Model simulations reveal a single steady state whose position on the glycolysis-OXPHOS phase plane depends on environmental conditions, namely, oxygen concentration, infection, and extracellular lactate. We identify four metabolic regimes, determined by sufficiency of energy production and the driving process (OXPHOS or glycolysis). Decreasing the oxygen shifts cells from OXPHOS to glycolysis dominance in both infected and non-infected states, but infected cells may become energy-deficient even with sufficient oxygen due to virus-induced mitochondrial damage. Rising extracellular lactate initially promotes glycolysis but ultimately suppresses it at high levels, pushing cells into severe energy deficit with inhibited glycolysis. Simulations of reoxygenation exhibit hysteresis: cells pass through an energy-deficient zone during hypoxia onset but return through a safer trajectory when oxygen is restored; a vulnerability is higher in infected cells. Overall, the model clarifies metabolic trajectories during viral infection, suggesting that early hypoxia is particularly dangerous and that severe acidosis can further collapse energy production. Preventing or rapidly reversing hypoxia in respiratory infection may protect cells from energy failure and limit harmful lactate accumulation.
    Keywords:  Glycolysis; HIF-1α ; Hypoxia; Reoxygenation; Viral infection
    DOI:  https://doi.org/10.1007/s00285-026-02441-y
  9. Cell Rep. 2026 Aug 01. pii: S2211-1247(26)00856-9. [Epub ahead of print]45(8): 117778
    MCT4-mediated lactate efflux promotes STING-dependent dendritic cell antitumor immunity.
    Rui Ding, Yaqing Yuan, Tongchang Xu, Jingwen Zhang, Yi Zhu, Bing Yao, Shuang Qu, Zhilin Hu.
      The mechanisms by which DCs evolutionarily adapt to lactate accumulation to maintain their functions remain largely elusive. Here, our study highlights the MCT4-lactate axis as an intrinsic metabolic checkpoint governing intratumoral DC activity. Intratumoral lactate supplementation impedes DC-dependent antitumor activity. Additionally, we observe that MCT4 is highly expressed in intratumoral DCs and mediates lactate efflux to boost DC function. Pharmacological or genetic inhibition of MCT4 suppresses DC antitumor responses. Mechanistically, MCT4-controlled lactate efflux sustains STING signaling and STING-dependent antitumor immunity. Loss of MCT4 in DCs augments lactate accumulation, subsequently reducing intracellular pH and disrupting the interaction between G3BP1 and cGAS, ultimately leading to impaired dsDNA sensing by cGAS. Importantly, the MCT4-lactate axis supports STING-dependent DC activity in ccRCC patient samples. Our findings uncover how intratumoral DCs adapt to lactate and suggest that targeting the MCT4-lactate axis represents a promising cancer immunotherapy strategy.
    Keywords:  CP: cancer; CP: immunology; MCT4; antitumor immunity; cGAS-STING; dendritic cells; lactate
    DOI:  https://doi.org/10.1016/j.celrep.2026.117778
  10. Immunometabolism (Cobham). 2026 Jul;8(3): e00088
    Meta-inflammation through the lens of macrophage programming and nutrient-sensing ghrelin signaling.
    Hye Won Han, Da Mi Kim, Sahar Eshghjoo, Chenxi Xu, Zeyu Liu, Bhimanagouda S Patil, Shaodong Guo, Yuxiang Sun.
      Macrophages are at the critical interface of immunity and metabolism. Metabolic reprogramming of macrophages, also known as meta-inflammation, has major implications in the pathogenesis of many chronic diseases. The infiltration and polarization of macrophages play critical roles in tissue homeostasis and inflammatory responses, thereby reshaping the tissue microenvironment. Macrophages have unique phenotypical and functional plasticity, making them attractive as therapeutic targets. Nutrient-sensing ghrelin is a gastrointestinal peptide hormone that functions through its receptor, growth hormone secretagogue receptor (GHSR), and is known to trigger hunger sensation, stimulate food intake, and promote fat deposition. Emerging evidence indicates that ghrelin/GHSR signaling is also a critical regulator of immunometabolism, modulating metabolic pathways in macrophages to enable their adaptation and functional responses to the tissue microenvironment. Here, we highlight the regulatory mechanisms of the ghrelin/GHSR system in macrophage reprogramming in meta-inflammation. In particular, we demonstrate the infiltration and differentiation of tissue-resident macrophages, and their functional impacts on the development and progression of metabolic and inflammatory dysfunctions. The dynamic and multifaceted roles of ghrelin/GHSR signaling in macrophage reprogramming could be leveraged to develop novel immunotherapies for meta-inflammatory conditions and diseases.
    Keywords:  ghrelin; growth hormone secretagogue receptor; immunometabolism; infiltration; macrophage reprogramming; meta-inflammation; polarization
    DOI:  https://doi.org/10.1097/IN9.0000000000000088
  11. J Leukoc Biol. 2026 Aug 03. pii: qiag106. [Epub ahead of print]
    The Pentose Phosphate Pathway in Immunotherapy.
    Rachel D Loo, John Blazeck.
      Emerging evidence has highlighted the influence of cellular metabolism on both cancer and T cell growth and survival, including in the context of adoptive cell immunotherapy. It is known that T cells heavily rely on glycolysis for cell proliferation and mediating effector functions. However, less is known about the role of the pentose phosphate pathway (PPP), a parallel metabolic pathway that produces antioxidant and biosynthetic precursors, towards regulating antitumor T cell function. In this review, we summarize the PPP's role as a time-dependent regulator of T cell activation and redox balance, and its association with improved functional capacity in exhausted T cells. We further highlight the contrasting role of the PPP for CD8+ and CD4+ T cell differentiation in guiding antitumor responses, as well as a unique connection in the glycogen-PPP axis to CD8+ memory T cells. Finally, we summarize global metabolic regulators that drive expression of PPP enzymes and discuss future avenues for immunotherapy that could take advantage of our current understanding of the PPP's role in T cell metabolism.
    Keywords:  T cell activation; T cells; antioxidants; cancer immunotherapy; glycolysis; pentose phosphate pathway
    DOI:  https://doi.org/10.1093/jleuko/qiag106
  12. J Immunol. 2026 Aug 04. pii: vkag206. [Epub ahead of print]215(8):
    Enforcing mTORC1 activity in therapeutic CD4+ T cells promotes persistence but eventual immune exhaustion.
    Francesca Sillito, Elisa Armbrecht, Aideen T O'Neill, Andrew McIntyre, Melville Nyatondo, Angelika Holler, Lauren A Callender, Sian M Henson, Hans Stauss, Ronjon Chakraverty.
      There is substantial interest in developing novel engineering strategies to promote the sustained metabolic fitness of therapeutic T cells. We previously showed that overexpression of RAS homologue enriched in brain (RHEB), a positive regulator of mammalian target of rapamycin complex 1 (mTORC1), promotes aerobic glycolysis and increases the anti-tumor functions of effector CD8+ T cells. To address whether these effects are conserved in CD4+ T cells, we have now examined how enforced activation of mTORC1 activity affects CD4+ T cell differentiation and function. Rheb overexpression induced a more balanced metabolic shift in CD4+ T cells than in CD8+ T cells, with increases in both oxidative phosphorylation and aerobic glycolysis. Although Rheb overexpression initially increased CD4+ T cell activation and proliferation in vitro, the underlying population architecture was complex, involving a shift to both more proliferative, cytotoxic-like cell states as well as more quiescent cell clusters characterised by counter-regulation of mTORC1 activity. Following adoptive transfer, tumor antigen-specific Rheb-transduced CD4+ T cells showed greater persistence but were less efficient than controls in eliminating tumor. This functional deficiency could be explained by a greater propensity of persisting Rheb-transduced CD4+ T cells to develop features of immune exhaustion, as evidenced by expression of multiple co-inhibitory receptors and impaired proliferation upon tumor rechallenge. Together, these data demonstrate the dynamic population response to tuning of T cell mTORC1 and the need to separately appraise cellular outputs of therapeutic CD4+ versus CD8+ T cells when metabolic pathways are manipulated by the same method.
    Keywords:  CD4+ T cell; exhaustion; immunotherapy; mTORC1
    DOI:  https://doi.org/10.1093/jimmun/vkag206
  13. Adv Sci (Weinh). 2026 Aug 05. e76968
    Stress Hyperglycemia Drives CD4+ T Cell PANoptosis and Postoperative Organ Injury via Monocyte-Derived Succinate.
    Shuai Zhao, Xuemei Miao, Wei Luo, Tao Liu, Yang Wang, Jiaying Li, Di Fu, Weiyun Shen, Yan Luo, Kang Chen, Ruping Dai, Hui Li.
      Perioperative stress hyperglycemia is a transient but frequent metabolic disturbance strongly linked to postoperative organ injury and mortality; however, the immunometabolic mechanisms driving this association remain largely undefined. In a two-center cohort of patients undergoing total aortic arch replacement, we identify stress hyperglycemia as an independent determinant of poor postoperative outcomes that associates strongly with CD4+ T cell loss. Hyperglycemia induces inflammatory PANoptosis in CD4+ T cells from patients in response to surgical trauma. This results from elevated glucose driving the accumulation and release of succinate from monocytes, which subsequently acts on CD4+ T cells to compromise mitochondrial integrity and activate ZBP1-mediated PANoptosis. Our findings define a monocyte-T cell metabolic signaling axis that transduces hyperglycemic stress via elevated succinate to adaptive immune cell death and reveal potential therapeutic targets to prevent postoperative immune dysfunction and organ injury, especially for patients with hyperglycemic comorbidities.
    Keywords:  CD4+ T cells; PANoptosis; aortic dissection; mitochondria; succinate
    DOI:  https://doi.org/10.1002/advs.76968
  14. Crit Rev Oncol Hematol. 2026 Aug 06. pii: S1040-8428(26)00417-8. [Epub ahead of print] 105530
    Mitochondrial transfer in the tumor microenvironment: mechanisms, immunometabolic consequences, and therapeutic implications.
    Sijia Feng, Yanan Hu, Shuqing Li, Yuqiao Chang, Zhenwei Li, Yanting Liu, Kai Xu.
      Mitochondrial transfer has emerged as a previously underappreciated layer of intercellular communication within the tumor microenvironment. Accumulating evidence demonstrates its contribution to the metabolic and functional plasticity of both tumor and immune cells. Rather than representing a rare stochastic event, mitochondrial exchange occurs across multiple cell types-including cancer cells, stromal cells, and infiltrating immune cells-via distinct structures such as tunneling nanotubes (TNTs), extracellular vesicles (EVs), gap junctions, and transient cell fusion events. In tumor cells, acquisition of exogenous mitochondria is commonly associated with enhanced oxidative phosphorylation (OXPHOS), improved metabolic adaptation, and increased tolerance to therapeutic stress. Conversely, immune cells that undergo mitochondrial depletion or receive dysfunctional mitochondria frequently display impaired bioenergetic capacity and diminished effector function, thereby contributing to immune dysfunction in the TME. Recent advances in intravital imaging, single-cell technologies, and lineage tracing have provided compelling evidence that mitochondrial transfer is a dynamic, context-dependent and often directional process. Beyond metabolic effects, mitochondrial components, particularly mitochondrial DNA (mtDNA), can engage innate immune pathways including TLR9, NLRP3, and cGAS-STING, thus modulating inflammatory signaling and antitumor immunity. Overall, mitochondrial transfer functions as a bidirectional regulator of immunometabolic states in cancer, with potential either to support tumor progression or to modulate immune responses, depending on cellular context. Understanding the molecular determinants governing this process may offer opportunities to selectively target pathological mitochondrial exchange or to exploit it for therapeutic benefit in cancer immunotherapy. This comprehensive review examines the molecular mechanisms, immunological consequences, and therapeutic implications of mitochondrial transfer in cancer.
    Keywords:  extracellular vesicles; metabolism; mitochondrial transfer; tumor immune microenvironment; tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105530
  15. Fish Shellfish Immunol. 2026 Oct;pii: S1050-4648(26)00519-X. [Epub ahead of print]177 111615
    Lactate facilitates largemouth bass virus replication by promoting cholesterol biosynthesis.
    Xixi Guo, Ting Yu, Yin Zhao, Guojun Pan, Youhua Huang, Qiwei Qin, Xiaohong Huang.
      Cellular metabolism has been hijacked by viruses for efficient replication due to their regulatory roles on both innate and adaptive immunity. Largemouth bass virus (LMBV), a member of Ranavirus, causes high mortality and severe economic losses in several fish species, seriously threatening the sustainable development of aquaculture industry. However, the roles of the metabolic events in LMBV replication remained largely uncertain. Here, our results showed that LMBV boosted aerobic glycolysis both in vitro and in vivo. Supplement with glucose significantly enhanced LMBV replication in vitro. Consistently, blocking glycolysis with 2DG or lactate biosynthesis with oxamate markedly decreased LMBV replication, as indicated by reduced viral gene expression, protein synthesis, and virus titers. Interestingly, exogenous lactate also significantly promoted LMBV replication. Mechanistically, lactate not only reduced interferon response triggered by poly(I:C), but also promoted cholesterol biosynthesis. Further analysis showed that lactate induced cholesterol biosynthesis might inhibit LMBV induced IRF3 phosphorylation, and reduce the expression levels of IFN-stimulated genes (e.g., IFN1, IFNγ, IRF3, IRF7, ISG20, MX). These findings suggest that lactate might facilitate LMBV replication by enhancing cholesterol biosynthesis and inhibiting host interferon response. Our results provided new insights into understanding the roles of metabolic reprogramming during iridovirus infection.
    Keywords:  Anti-viral; Cholesterol; IFN response; Lactate; Largemouth bass virus (LMBV)
    DOI:  https://doi.org/10.1016/j.fsi.2026.111615
  16. Front Immunol. 2026 ;17 1927032
    Editorial: Metabolite-induced metabolic reprogramming in the immune system.
    Jacqueline Oliva-Ramírez, Heriberto Prado-Garcia, Francisco Javier Sánchez-García.
      
    Keywords:  immunity; immunometabolism; metabolic reprogramming; metabolite intervention; metabolite signaling
    DOI:  https://doi.org/10.3389/fimmu.2026.1927032
  17. Immunity. 2026 Aug 06. pii: S1074-7613(26)00306-7. [Epub ahead of print]
    Virus-induced deconjugation of ISG15 dysregulates innate immunity and cellular metabolism.
    Junji Zhu, GuanQun Liu, Jielin Xu, Zuberwasim Sayyad, Kun Li, Surajit Chakraborty, Christopher M Goins, Huaxu Yu, Yadi Zhou, Shanti Ross, Evangeline White, Jun Zhao, Oliver Fiehn, Shaun R Stauffer, Feixiong Cheng, Michaela U Gack.
      Interferon-stimulated gene 15 (ISG15) encodes a ubiquitin-like protein that regulates diverse cellular responses, including antiviral immunity, through its conjugation to proteins in a process known as ISGylation. Several pathogens, including SARS-CoV-2, subvert ISGylation by encoding deISGylating enzymes. However, the direct targets and physiological consequences of coronaviral deISGylation remain poorly defined. Here, we genetically ablated the deISGylating activity of the SARS-CoV-2-encoded papain-like protease (PLpro) and found that loss of deISGylation boosted innate immune activation, attenuated viral replication, and promoted viral clearance in human cells and mice. Metabolomics, ISGylome proteomics, and functional analyses revealed that PLpro deISGylation relieved metabolic restriction of virus infection by directly regulating the activity of key enzymes controlling glycolysis, the pentose phosphate pathway, and redox homeostasis. These findings provide fundamental insight into how reversible ISGylation regulates immunity and metabolic processes at the molecular level and highlight viral deISGylation as a major strategy to overcome host immunometabolic defenses.
    Keywords:  ISG15; ISGylation; PLpro; SARS-CoV-2; innate immunity; interferon; metabolism
    DOI:  https://doi.org/10.1016/j.immuni.2026.07.007
  18. Front Immunol. 2026 ;17 1855111
    Fetal sex shapes maternal immune adaptation: placental extracellular vesicles differentially reprogram the phenotype, metabolism, and function of circulating monocytes.
    Julieta Avalos, Florencia Sabbione, Daiana Rios, Daniel H Grasso, M Noe Garcia, Franco Aguilera, Fatima Merech, Horacio Aiello, Cesar Meller, Rosanna Ramhorst, Vanesa Hauk, Soledad Gori, Claudia Pérez Leirós, Daiana M Vota, Daniel E Paparini.
       Introduction: Maternal immune adaptation during pregnancy is orchestrated by dynamic signals from the uterine microenvironment, including placental extracellular vesicles (pEVs) released into maternal circulation. EVs have emerged as key mediators of this crosstalk; however, their role in sex-specific immune modulation remains incompletely defined. Here, we investigated whether pEVs derived from term placentas induce sex-dependent changes in the phenotype, metabolism, and function of human monocytes.
    Methods: pEVs were isolated from 13 term uncomplicated placentas (six male-derived, M-pEVs, and seven female-derived, F-pEVs) and characterized by complementary approaches, revealing similar size distributions and concentrations, with differences in physicochemical properties and molecular cargo. Circulating monocytes from 17 non-pregnant female donors were exposed to M-pEVs or F-pEVs and analyzed for phenotypic, metabolic, and functional responses.
    Results: pEVs induced distinct activation profiles depending on fetal sex. F-pEVs reduced CD11b and CD11c expression while increasing CD14, CD39 and IL-10 production. On the other hand, M-pEVs increased CD14 expression and enhanced IL-1β secretion. Both nanovesicles populations increased IL-10 and CXCL8 release and promoted a shift toward classical monocytes (CD14+CD16-) with a reduction in the intermediate subsets. Metabolic analyses revealed divergent immunometabolic programs: M-pEVs promoted lactate and reactive oxygen species production, whereas F-pEVs enhanced lactate production, fatty acid uptake, lipid droplet accumulation, and mitochondrial activity without increasing ROS. Functionally, both pEV populations increased efferocytosis, with a distinct sensitivity to metabolic inhibitors.
    Discussion: These findings demonstrate that pEVs differentially modulate circulating monocytes according to fetal sex and support a role for fetal sex in shaping maternal immunometabolic responses.
    Keywords:  extracellular vesicles; immunometabolism; macrophages; monocyte; pregnancy; sex-differences
    DOI:  https://doi.org/10.3389/fimmu.2026.1855111
  19. Front Immunol. 2026 ;17 1892919
    HPV-driven metabolic reprogramming promotes T cell exhaustion: targeting immunometabolic barriers with natural products.
    Liang Wei, Hou Menghui, Zhang Dandan, Wang Xin, Chu Xinying, Ma Guangyi, Ma Jing.
       Background: High-risk human papillomavirus (HR-HPV) infection is the primary driver of cervical cancer. Emerging evidence indicates that the tumor microenvironment (TME) undergoes severe metabolic rewiring, which may accelerate T cell exhaustion (TEX) and impair immune checkpoint blockade (ICB). However, the molecular mechanisms coupling HPV-driven metabolism to T cell dysfunction remain incompletely elucidated.
    Methods: This review summarizes immunometabolic interactions in the cervical cancer TME. We examined the metabolic alterations induced by HPV oncoproteins (E6/E7) and how they reshape nutrient availability, lactate accumulation, and lipid peroxidation to drive anti-tumor CD8+ T cell exhaustion.
    Results: HPV-driven aerobic glycolysis and IDO1-mediated tryptophan catabolism establish severe metabolic barriers, causing nutrient deprivation and histone lactylation in infiltrating lymphocytes. These alterations are associated with persistent mitochondrial stress and ferroptosis, accelerating terminal TEX. In preclinical models, natural products (e.g., curcumin, berberine, quercetin, and artemisinin derivatives) can counteract this immunosuppressive rewiring by targeting checkpoints such as HIF-1α, PKM2, and AMPK; however, direct evidence of CD8+ tumor-infiltrating lymphocyte rescue in HPV-specific immune-competent systems remains limited, largely inferred from other tumor types. Nanomedicine delivery may further enhance the bioavailability and targeting of these herbal components.
    Conclusion: HPV-induced metabolic reprogramming is proposed to act as a fundamental checkpoint driving T cell exhaustion in cervical cancer. Targeting these immunometabolic barriers using natural compounds, particularly via nanomedicine-based delivery strategies, represents a promising but still largely preclinical avenue to synergize with conventional immunotherapies and potentially overcome resistance.
    Keywords:  T cell exhaustion; cervical cancer; human papillomavirus; metabolic reprogramming; natural products; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1892919
  20. Exp Mol Med. 2026 Aug 06.
    Metabolic rewiring of the dendritic cell-T cell axis: tumour-derived barriers and therapeutic opportunities.
    Minkyu Cho, Minkyung Song.
      The tumour microenvironment imposes severe metabolic constraints that reshape anti-tumour immunity across the cancer-immunity cycle. Rather than serving merely as passive byproducts of tumour growth, tumour-derived metabolites and nutrient imbalances act as potent metabolic checkpoints-stage-specific barriers that disrupt the functional progression of dendritic cells (DCs) and T cells from antigen presentation to effective tumour clearance. In this review, we propose a framework that overlays the cancer-immunity cycle with major metabolic checkpoints, including glucose and amino acid competition, acidosis and lipid overload, to clarify how distinct metabolic stresses create immune bottlenecks at different stages of the anti-tumour response. We then discuss how distinct tumour metabolic phenotypes, characterized by high glycolysis, amino acid dependency or lipid dysregulation, generate local environmental stresses that differentially reprogram DC function and T cell fitness. Particular emphasis is placed on the DC-T cell axis as a critical site where multiple metabolic defects converge, destabilizing antigen presentation, co-stimulation and immunological synapse function. We further survey emerging therapeutic strategies aimed at restoring the DC-T cell axis and effective anti-tumour immunity, ranging from small-molecule metabolic inhibitors to metabolically engineered adoptive cell therapies designed to function in hostile microenvironments. Finally, we highlight emerging technologies such as single-cell and spatial multi-omics, real-time metabolic imaging and microphysiological systems that can resolve the spatiotemporal heterogeneity of tumour immunometabolism and support more precise immunometabolic interventions.
    DOI:  https://doi.org/10.1038/s12276-026-01798-w
  21. Front Immunol. 2026 ;17 1876507
    Reframing macrophage polarization through cholesterol efflux: an organelle-coupled immunometabolic model.
    Ya Zou, Yun Lu, Lu Zhou, Qinchuan Li, Hua Wei, Yan Zhou, Shibo Lin, Xirui Guo, Shihao Yan, Hongju Wang, Fangqing Xie, Chun Liu.
      Macrophages reside at the interface of immunity and metabolism, where their functional states are traditionally described by the M1/M2 polarization paradigm. However, this binary framework fails to capture the dynamic integration between inflammatory signaling and lipid metabolism that underlies macrophage behavior in chronic diseases. A central unresolved question is why macrophages, under sustained inflammatory and metabolic stress, progressively lose their capacity to maintain cholesterol homeostasis. Here, we propose a conceptual framework that is not merely a reinterpretation of existing data but a testable model: the macrophage polarization-efflux coupling axis, in which macrophage functional states are governed by the coordinated integration of lipid metabolism and organellar homeostasis, particularly the mitochondria-lysosome axis. Current evidence suggests that impaired cholesterol efflux may function as an active driver, rather than merely a downstream consequence, of macrophage dysfunction, based on evidence showing that genetic or pharmacological restoration of efflux actively repolarizes inflammatory macrophages toward a resolving phenotype. Lipid accumulation is reframed as a consequence of system-level failure arising from mismatched mitochondrial energy metabolism and lysosomal processing capacity. We further synthesize evidence demonstrating how transcriptional regulators, microRNA networks, epigenetic memory, and post-translational modifications converge to stabilize this dysfunctional state across diseases such as atherosclerosis and diabetic kidney disease. Importantly, emerging therapeutic strategies that restore organellar integrity and metabolic coordination show greater promise than approaches solely targeting inflammatory polarization. This integrative perspective shifts the focus from static phenotypic classification toward dynamic metabolic-organelle coupling, providing a unifying framework for understanding macrophage dysfunction and identifying novel therapeutic opportunities.
    Keywords:  atherosclerosis; cholesterol efflux; diabetic kidney disease; immunometabolism; macrophage polarization; mitochondria-lysosome axis; organelle homeostasis
    DOI:  https://doi.org/10.3389/fimmu.2026.1876507
  22. Inflamm Res. 2026 Aug 04. pii: 187. [Epub ahead of print]75(1):
    Context-dependent lysophosphatidic acid signalling in inflammation: evidence hierarchy, myeloid regulation and translational gaps.
    Wataru Nagata, Kunio Takada.
       BACKGROUND: Lysophosphatidic acid (LPA) has been extensively reviewed in receptor pharmacology, fibrosis, cancer, vascular biology and neural injury. Its role in inflammation remains difficult to interpret because well-replicated pathogenic or pro-remodelling actions coexist with selected macrophage-regulatory effects reported under defined experimental conditions.
    FINDINGS: This structured narrative review provides an evidence-weighted framework for interpreting these divergent findings. The strongest evidence supports LPA as an injury- and remodelling-associated signal in vascular-stromal programmes, pain-associated settings and tumour immune escape. By contrast, LPA-mediated attenuation of selected LPS/TLR4-driven macrophage responses is biologically plausible but incompletely replicated and receptor-divergent. The more specific LPAR1-dependent model of M2-like and metabolic macrophage reprogramming remains less independently validated, especially in primary human myeloid cells and physiologically plausible concentration ranges.
    CONCLUSIONS: LPA should not be classified as simply pro-inflammatory or anti-inflammatory. Anti-inflammatory LPA models should be regarded as experimentally plausible but translationally unproven until validated using defined LPA species, receptor-resolved perturbation and concentration-resolved human myeloid-cell systems.
    Keywords:  Autotaxin; Immunometabolism; LPA receptor; Lysophosphatidic acid; Macrophage; Microglia
    DOI:  https://doi.org/10.1007/s00011-026-02337-z
  23. Nat Rev Rheumatol. 2026 Aug 03.
    Metabolic exhaustion and immune ageing in rheumatoid arthritis.
    Cornelia M Weyand, Jörg J Goronzy.
      Rheumatoid arthritis (RA) disproportionately affects adults over 50 years of age, highlighting how age-related immune remodelling undermines tolerance and promotes autoreactivity. In later adulthood, immune cells progressively lose metabolic resilience because of impaired nutrient sensing, reduced metabolic flexibility and disrupted anabolic-catabolic balance. In RA, these vulnerabilities are compounded by mitochondrial insufficiency across innate and adaptive immune lineages, creating a state of nutrient deprivation characterized by NAD⁺ and ATP scarcity and diversion of carbon away from oxidative phosphorylation. Mechanistic studies identify this bioenergetic fragility as a core defect that limits cellular longevity and promotes inflammatory, non-apoptotic death pathways, including pyroptosis and PANoptosis. The hypoxic, nutrient-restricted synovial environment adds pressure that exceeds the diminished metabolic adaptability of aged immune cells. In RA T cells, accelerated mitochondrial injury initiates maladaptive stress responses, disrupts mitochondria-lysosome-endoplasmic reticulum communication and induces gasdermin D-dependent pore formation and inflammatory lysis. Synovial MerTK⁺ reparative macrophages undergo a parallel metabolic crisis, whereby autocrine C1q sensing activates mitochondrial SARM1, causing NAD⁺ degradation, ATP depletion and PANoptotic cell death. Together, these findings position ageing-associated metabolic exhaustion and organelle disintegration as unifying mechanisms that convert immune cells into tissue-damaging effectors and explain the heightened susceptibility to RA in older adults.
    DOI:  https://doi.org/10.1038/s41584-026-01402-5
  24. Curr Opin Hematol. 2026 Jul 28.
    Inflammation as a pleiotropic regulator of megakaryocyte and platelet hemostatic, immune, and metabolic function.
    Guadalupe Rojas-Sanchez, Pavel Davizon-Castillo.
       PURPOSE OF REVIEW: During infectious and noninfectious inflammatory diseases, disruption of the immune-hemostatic balance increases both thrombotic and hemorrhagic risk. We propose that this bidirectional dysregulation reflects the integrated contribution of megakaryocyte reprogramming during thrombopoiesis and direct remodeling of circulating platelets by inflammatory mediators, two interconnected regulatory levels that together shape the prothrombotic and hemorrhagic platelet phenotypes observed across inflammatory conditions.
    RECENT FINDINGS: Current evidence supports a two-level framework through which inflammation remodels platelet responses. Upstream, recent studies demonstrate that inflammation remodels thrombopoiesis, megakaryocyte transcriptional programs, and immunometabolism, generating platelets with altered immunothrombotic, thromboinflammatory, and prothrombotic properties. Converging evidence from aging, sepsis, myeloproliferative neoplasms, and rheumatoid arthritis identifies autophagy as a central target of inflammatory signaling linking megakaryocyte and platelet reprogramming to mitochondrial dysfunction and impaired clot contraction. Downstream, inflammatory mediators directly remodel platelet receptor signaling and promote receptor transfer, generating context-dependent platelet functional states that contribute to both thrombotic and hemorrhagic complications.
    SUMMARY: The platelet phenotype observed across inflammatory diseases reflects the integrated contribution of megakaryocyte reprogramming during thrombopoiesis and direct remodeling of circulating platelets by inflammatory mediators. These two levels of regulation likely operate simultaneously and may amplify each other, yet how they interact to determine platelet functional outcomes in specific inflammatory contexts remains to be determined. Defining these interactions will inform the development of mechanism-based therapeutic strategies that target inflammation-driven platelet dysfunction to reduce thrombotic and hemorrhagic complications across inflammatory diseases.
    Keywords:  immunometabolism; immunothrombosis; inflammation; megakaryocytes; platelets
    DOI:  https://doi.org/10.1097/MOH.0000000000000943
  25. Front Immunol. 2026 ;17 1887842
    Integrating T cell signaling and metabolism to enhance T cell engager responses in solid tumors.
    Michael Scaglione, Minal Engavale, Matthew G Chun, Deepali V Sawant, Daniel R Lu, Edward LaGory.
      T cell engagers (TCEs) have delivered meaningful clinical benefit to patients, with eight molecules currently FDA-approved for hematologic malignancies and two approved for solid tumor indications. Despite their transformative potential, successful TCE development across solid tumor indications remains challenging, and additional strategies are needed to maintain T cell fitness and function within the tumor microenvironment (TME). Next-generation TCE designs aim to increase response rate and bolster durability by optimizing or delivering additional signals to T cells. In recent years, cellular metabolism has emerged as a potent regulator of T cell function and fate, shaping immunity by supporting the biochemical requirements of immunological effector functions and acting as a direct immunoregulatory signal from the TME itself. Despite this, neither cell-intrinsic nor environmental roles for metabolism in regulating TCE responses in solid tumors have been explicitly explored. We propose that metabolism is a powerful lens for understanding TCE efficacy and resistance in solid tumors, integrating signals from both surface receptors and the biochemical environment of the TME to shape T cell function and therapeutic response. In this mini-review, we highlight how three classical T cell signaling axes - 1) the T cell receptor complex, 2) costimulatory receptors, and 3) cytokine receptors - drive metabolic rewiring to license immune function and shape T cell fate. We also explore how environmental cues such as nutrients or metabolic stressors govern T cell responses, highlighting how biochemical perturbations within the TME could hamper TCE efficacy. Finally, we highlight emerging methods for dissecting metabolic contributions to TCE responses, proposing that understanding the interplay between immunological signaling, cellular metabolism, and immune programming could inform the design of next-generation TCEs for solid tumors.
    Keywords:  T cell engagers (TCEs); immunotherapy; metabolism; signaling; solid tumors; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fimmu.2026.1887842
  26. PLoS Pathog. 2026 Aug 05. 22(8): e1014471
    Epigenetic and metabolic reprogramming of innate immune cells establishes immunological memory in the Schistosomiasis vector snail Biomphalaria glabrata.
    Rémi Pichon, Silvain Pinaud, Cristian Chaparro, Manon Fallet, Ricardo Lebron, Jean-François Allienne, Evgenia Turtoi, Christoph Grunau, Andrei Turtoi, David Duval, Richard Galinier, Céline Cosseau, Benjamin Gourbal.
      Innate immune memory enables non-vertebrates to mount faster and more effective immune responses upon re-exposure to a previously encountered pathogen, yet its cellular and molecular bases remain poorly understood. The freshwater snail Biomphalaria glabrata, intermediate host of the human parasite Schistosoma mansoni, provides a powerful model to investigate this phenomenon. Here, we show that innate immune memory in B. glabrata is carried by hemocytes and relies on profound metabolic and epigenetic reprogramming initiated during primary infection. Using an integrative multi-omics approach combining transcriptomics, chromatin accessibility profiling, whole-genome bisulfite sequencing and targeted metabolomics, we reveal that the first parasite encounter induces a stable rewiring of hemocyte metabolism and chromatin landscape. This reprogramming primes hemocytes for a massive and rapid transcriptional response upon secondary challenge, characterized by an immune shift toward highly specific humoral effector pathways. Metabolic analyses demonstrate an early switch toward aerobic glycolysis, altered tricarboxylic acid cycle activity and amino acid metabolism, consistent with a Warburg-like metabolic state previously described in vertebrate trained immunity. Notably, metabolic and epigenetic remodeling occurs primarily during the primary infection and remains stable upon secondary exposure, suggesting that immune memory is encoded prior to pathogen re-encounter. Together, our results identify conserved metabolic and epigenetic mechanisms underlying innate immune memory in a non-vertebrate host and provide direct evidence that hemocyte-mediated innate immune memory in B. glabrata shares core features with trained immunity described in vertebrates.
    DOI:  https://doi.org/10.1371/journal.ppat.1014471
  27. Atherosclerosis. 2026 Jul 27. pii: S0021-9150(26)01224-4. [Epub ahead of print]420 121858
    Lactate promotes macrophage-derived foam cell formation and atherosclerosis.
    Zhenzhen Jia, Shuaiyin Liu, Zhifeng Yang, Xinmiao Chen, Yichen Liu, Shuguang Li, Junlin Chen, Xinxing Feng, Xufeng Niu, Wei Wang.
       BACKGROUND AND AIMS: Diabetes accelerates atherosclerosis progression by disrupting multiple metabolic pathways. However, the role and mechanisms of lactate-a glycolytic byproduct significantly elevated in diabetic patients-in atherosclerosis remain poorly understood. We hypothesized that lactate promotes atherosclerosis by regulating macrophage foam cell formation through histone lactylation.
    METHODS: We evaluated the association between lactate levels, lipid metabolism disorders, and atherosclerotic progression using clinical samples and mouse models. The thoracic aortas of atherosclerotic mice were subjected to ex vivo culture to investigate the impact of lactate on the microenvironment within atherosclerotic plaques. Foam cell models were established using human and murine macrophages, and intracellular lipid accumulation, inflammatory responses, and apoptosis were assessed following lactate treatment. RNA sequencing was performed to dissect the molecular mechanisms underlying lactate-induced foam cell formation.
    RESULTS: Results demonstrated that lactate promoted foam cell formation and contributed to atherosclerotic progression by enhancing intracellular lipid accumulation, pro-inflammatory cytokine secretion, and apoptosis in macrophages. RNA-seq analysis revealed that lactate significantly modulated pathways related to atherosclerosis and lipid metabolism, specifically inhibiting cholesterol efflux pathways during foam cell formation. Lactate increased H3K18la enrichment at the promoters of cholesterol efflux genes, accompanied by reduced expression of ABCA1, ABCG1, and SR-B1 and enhanced lipid accumulation. Notably, magnesium ions attenuated these lactate-associated effects and reduced intracellular lactate accumulation in macrophages.
    CONCLUSIONS: Lactate contributes to atherosclerosis progression by enhancing foam cell formation and histone lactylation in macrophages, an effect mitigated by Mg2+. These findings identify lactate as a potential contributor to atherosclerosis progression and provide mechanistic insights into lactate-associated metabolic regulation in macrophages.
    Keywords:  Atherosclerosis; Foam cell; Lactate; Macrophage; Magnesium
    DOI:  https://doi.org/10.1016/j.atherosclerosis.2026.121858
  28. Acta Pharmacol Sin. 2026 Aug 04.
    PGK1-driven histone lactylation fuels MDSC-driven immune evasion and tumor progression in triple-negative breast cancer.
    Yong-Peng Wang, Wen-Zhen Dang, Zhen-Dan Liu, Bing Li, Huan Xiong, Hudagula Bai, Xiao Li, Shuo Wu, Cheng Luo, Wei-Lie Xiao, Yuan-Yuan Zhang.
      Metabolic reprogramming and immune regulation are tightly interconnected processes that critically influence cancer progression. The efficacy of immunotherapy is limited in triple-negative breast cancer (TNBC) by metabolic abnormality and immunosuppressive microenvironment. However, the molecular mechanisms through which these alterations cooperate to drive immune evasion and tumor progression in TNBC remain poorly defined. Through transcriptomic profiling, we identified glycolysis and chemokine signaling as the dominant intersecting metabolic and immune pathways that distinguish TNBC from non-TNBC subtypes. Phosphoglycerate kinase 1 (PGK1) is associated with poor prognosis and with myeloid-derived suppressor cells (MDSCs), acting as a key metabolic node linking metabolic regulation to immune modulation. Functionally, PGK1 knockdown inhibited tumor growth in vitro and in vivo and reduced MDSC recruitment. Notably, PGK1 knockdown exerted a more pronounced antitumor effect under immune surveillance, accompanied by decreased infiltration of both monocytic and polymorphonuclear MDSCs and recovered CD8+ T cell function. Mechanistically, PGK1 increased lactate production and global lysine lactylation. Notably, histone H3 lysine 18 lactylation (H3K18la) at the CCL5 promoter served as a dominant and required epigenetic modification for PGK1-driven CCL5 transcription, thereby driving CCL5-dependent MDSC recruitment. P300 and class I HDACs were identified as candidate "writer" and "eraser" enzymes for PGK1-dependent H3K18la modification. Notably, combining the PGK1 inhibitor ABT-E79 with anti-PD-1 therapy synergistically decreased MDSC infiltration, recovered CD8+ T cell function, and elicited superior antitumor responses compared to monotherapy. Collectively, this study shows a mechanistic link between metabolic reprogramming and immune evasion, offering new therapeutic insights for TNBC. Starting from analyzing metabolic and immunological signaling pathways in cancers lacking clear therapeutic targets and treatment options, we aimed to identify metabolism-associated regulators of immune responses as potential therapeutic targets. Focusing on triple-negative breast cancer (TNBC), through transcriptomic profiling, we identified glycolysis and chemokine signaling as the dominant intersecting metabolic and immune pathways that distinguish TNBC from non-TNBC subtypes. Functional assays demonstrated that PGK1-driven glycolysis in TNBC cells promotes lactate accumulation and H3K18la, which subsequently induce transcriptional activation of CCL5 and recruitment of MDSCs, thereby impairing CD8+ T cell function and fostering an immunosuppressive tumor microenvironment that facilitates immune evasion. Furthermore, treatment with ABT-E79, a PGK1 inhibitor, enhances the antitumor immune efficacy of anti-PD-1 therapy.
    Keywords:  MDSC; PGK1; TNBC; chemokine; glycolysis
    DOI:  https://doi.org/10.1038/s41401-026-01875-w
  29. Mol Biomed. 2026 Aug 08. pii: 133. [Epub ahead of print]7(1):
    Distinct immunometabolic signatures in peripheral blood mononuclear cells are linked to systemic inflammation in type 2 diabetes and diabetic kidney disease.
    Clara Luna-Marco, José F Català-Senent, Julia Cacace, Alberto Hermo-Argibay, Omar A Hernández-López, María Pelechá-Salvador, Jonay Pantoja, Asunción Sancho, Jose M Vila, Carlos Morillas, Celia Bañuls, Milagros Rocha, Víctor M Víctor, Susana Rovira-Llopis.
      Diabetic kidney disease (DKD) is a frequent complication of type 2 diabetes and is closely linked to systemic inflammation. Peripheral blood mononuclear cells (PBMCs) are markers of systemic inflammatory and metabolic stress. It is unknown if metabolism-related transcriptomic alterations in these cells is associated with DKD. Using the nCounter® Human Metabolic Pathways Panel we profiled PBMC metabolic transcripts in individuals with type 2 diabetes or DKD and in controls (n = 12/group), and integrated transcriptomic data with clinical, inflammatory, and mitochondrial parameters. Patients with DKD showed increased inflammatory biomarkers and reduced PBMC mitochondrial membrane potential and mass, consistent with mitochondrial dysfunction. Metabolism-related transcriptomic profiling identified 13 differentially expressed genes across groups. DKD subjects displayed downregulation of SLC7A11 versus controls and HLA-DQA1 versus type 2 diabetes, and upregulation of CPT1A and GBA1 versus controls. CPT1A upregulation was confirmed by RT-qPCR and supported by external GEO datasets, though ROC analyses indicated a limited discriminatory performance. Pathway analyses revealed enrichment of immune-related, fatty acid oxidation, and fructose-6-phosphate pathways and reduced cell proliferation pathways in DKD patients. Inflammatory markers correlated positively with energy-regulating pathways and negatively with anabolic processes. In conclusion, these findings suggest that PBMCs reflect immunometabolic remodeling in response to DKD, thus highlighting an association between systemic inflammation, mitochondrial dysfunction, and altered energy metabolism in circulating immune cells.
    Keywords:  Diabetic kidney disease; Immunometabolism; Inflammation; Peripheral blood mononuclear cells (PBMCs); Transcriptomic profiling; Type 2 diabetes
    DOI:  https://doi.org/10.1186/s43556-026-00523-3
  30. Vet Microbiol. 2026 Jul 31. pii: S0378-1135(26)00297-X. [Epub ahead of print]321 111160
    Arginine downstream metabolites spermidine and putrescine, but not spermine, contribute to PCV2 replication.
    Jianwei Zhou, Haoyu Sun, Beiyi Zhou, Xiaoyuan Lan, Weiyin Xu, Peng Hui, Qianqian Zhang, Xue Dong, Wei Gao, Yonghui Qiu, Dedong Wang, Yongqiu Cui, Jinshuo Guo, Lei Hou, Jue Liu.
      Porcine circovirus type 2 (PCV2), a major pathogen of PCV2-associated diseases, causes immense economic losses. Understanding the cellular metabolic reprogramming induced by viruses provides novel clues for screening antiviral drugs. However, until now, no reports have described the cellular metabolic profile during PCV2 infection. In this study, we performed untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomic analysis of PCV2-infected PK-15 cells, and found that PCV2 infection upregulated significantly arginine and its metabolite spermidine. Further, we found that arginine downstream metabolites spermidine and putrescine markedly promoted PCV2 replication and played a proviral role during the replication stage of PCV2 infection. Difluoromethylornithine (DFMO)-an ornithine decarboxylase 1 (ODC1) inhibitor-decreases endogenous polyamine levels, and its treatment suppressed PCV2 replication. Supplementation with exogenous spermidine or putrescine, but not spermine, strikingly facilitated PCV2 replication, and inhibition of polyamine biogenesis significantly curtailed PCV2 replication in vitro and in the murine model. Taken together, the study revealed that spermidine plays an important proviral role in PCV2 replication and suggests that cellular polyamine metabolism is a suitable target for therapeutic intervention against PCV2 infection.
    Keywords:  Metabolic reprogramming; Polyamine metabolism; Porcine circovirus type 2; Spermidine and putrescine; Viral replication
    DOI:  https://doi.org/10.1016/j.vetmic.2026.111160
  31. Front Immunol. 2026 ;17 1827119
    Pyruvate kinase M2 is elevated in systemic sclerosis and plays a role in its pathogenesis.
    Thomas Steadman, Steven O'Reilly.
       Background: Systemic sclerosis is an autoimmune fibrotic skin disease characterised by immune activation and fibrosis. Fibroblasts are at the core of this fibrotic process, differentiating into effector myofibroblasts; however, the drivers of this process remain obscure. Recently, metabolic changes in cells in fibrotic diseases have been uncovered, with changes in the TCA cycle and glycolysis being observed.
    Objective: The objective of this work was to elucidate the role of the glycolytic enzyme pyruvate kinase M2 (PKM2) in systemic sclerosis.
    Methods: Serum from early diffuse systemic sclerosis (SSc) patients and healthy controls (HC) was collected for PKM2 analysis by ELISA. Fibroblasts were isolated from HC and SSc biopsies and treated with transforming growth factor-beta 1 (TGF-β1) to assess PKM2 expression. PKM2 was pharmacologically modulated, and collagen and Extracellular Matrix (ECM) regulators were evaluated. Metabolic activity was assessed using Seahorse assays, and lactate transport was chemically inhibited. Chromatin immunoprecipitation was performed using a histone lactylation-specific or isotype antibody, and lactate or acetate supplementation experiments were conducted.
    Results: We found significantly elevated circulating and fibroblast PKM2 in SSc patients. Fibroblast PKM2 could be induced in healthy fibroblasts by TGF-β1 exposure. Furthermore, PKM2 drives a metabolic shift to glycolysis that can be blocked by forced tetramerisation of PKM2 from its dimeric form; this resulted in reduced ECM and matrix regulators. Mechanistically, PKM2-mediated glycolysis results in elevated lactate, which drives collagen via epigenetic regulation by histone H3K18 lactylation. Blockade of PKM2 dimerisation reduced Histone H3 at Lysine 18 (H3K18) lactylation at the collagen promoter, which could be restored with lactate but not acetate. We further demonstrated that lactate-induced collagen is partially mediated by HIF-1α.
    Conclusion: PKM2 drives activation of fibroblasts in SSc via metabolic changes such as glycolysis. Taking advantage of PKM2 tetramerisation or blockade of lactate generation could be a possible therapeutic option in a disease with few treatment options.
    Keywords:  PKM2; epigenetics; fibroblast; fibrosis; lactylation; metabolism; systemic sclerosis
    DOI:  https://doi.org/10.3389/fimmu.2026.1827119
  32. Front Immunol. 2026 ;17 1867909
    Sarcopenia and sepsis fuel a self-perpetuating cycle of immunometabolism decline.
    Elisa Gouvea Gutman, Renan Muniz-Santos, Adilson Moreira da Silva, Giovanna Lucieri Alonso Costa, Carolina Medina Coeli da Cunha, Bianca Portugal Tavares de Moraes, Cassiano Felippe Gonçalves de Albuquerque.
      Sepsis and sarcopenia are intertwined clinical challenges characterized by profound immunometabolic dysregulation. Traditionally viewed as a passive reservoir, skeletal muscle is now recognized as an active immunometabolic rheostat that dynamically influences systemic inflammation and homeostasis. This review synthesizes recent advances that redefine our understanding of muscle in critical illness, moving beyond simplistic views of catabolism to encompass complex adaptive strategies. This review summarizes recent advances and discusses septic autocannibalism, a process in which muscle proteolysis, driven by a metabolic defense priority, provides key substrates, glutamine for immune function and alanine for hepatic gluconeogenesis. Initially adaptive, sustained activation of this response leads to severe muscle wasting and long-term functional impairment. We analyze the bidirectional relationship between these conditions, focusing on shared risk factors such as immunosenescence and obesity. Key molecular pathways, including the IL-6/JAK/STAT and NF-κB axes, are examined, with particular emphasis on how the temporal release of myokines (e.g., IL-6, IL-15, IGF-1) dictates their shift from adaptive signals to chronic catabolic drivers. Furthermore, we discuss how energy reprogramming, characterized by aerobic glycolysis and mitochondrial failure, disrupts muscle homeostasis. We highlight physical activity as a potent modulator of immunometabolic health through the release of anti-inflammatory myokines and enhanced mitochondrial biogenesis. To propel the field forward, we propose experimental avenues: single-cell spatial transcriptomics to map cellular crosstalk, mitochondrial transplantation to restore energetic capacity, and the identification of "muscle resilience" biomarkers for early intervention. This review underscores the urgent need for integrated immunometabolic approaches to improve outcomes in critically ill patients.
    Keywords:  immunometabolism; muscle-immune crosstalk; myokines; sarcopenia; sepsis; skeletal muscle
    DOI:  https://doi.org/10.3389/fimmu.2026.1867909
  33. Exp Mol Med. 2026 Aug 05.
    Macrophage-to-myofibroblast transition-derived itaconate promotes bone metastasis in lung cancer through targeting of HSPA8.
    Jin Qian, Zhidan Tan, Jinfeng Wang, Tiantian Wei, Chongquan Huang, Shi Cheng, Guoqing Zhong, Huizhen Zou, Xia Kang, Linchong Sun, Yu Zhang.
      Lung cancer bone metastasis carries a poor prognosis, yet the metabolic determinants driving tumour-stroma crosstalk remain largely elusive. Despite extensive investigations into itaconate, a prominent immunometabolite implicated in macrophage polarization, the precise mechanisms by which it modulates bone metastasis remain unresolved. Integrating metabolomics and transcriptomics profiling, the molecular landscape of lung cancer bone metastasis is delineated and the mechanistic role of itaconate is uncovered. Further ubiquitination proteomics of tumour cells and CRISPR-Cas9-mediated knockout of the gene encoding immune-responsive gene 1 (IRG1) confirmed the results in an animal model of lung cancer bone metastasis. The macrophage-to-myofibroblast transition generated cancer-associated fibroblasts that secreted elevated levels of itaconate, significantly accelerating tumour growth. A drug affinity responsive target stability screening pinpointed heat shock protein family A member 8 (HSPA8) as a direct molecular target of itaconate. Mechanistically, itaconate promoted HSPA8 ubiquitination and subsequent proteasomal degradation, thereby releasing activated transcription factor 4 (ATF4) from cytosolic sequestration. Liberated ATF4 translocated to the nucleus, where it bound the promoter region of phosphoserine aminotransferase 1 (PSAT1) to upregulate its expression. In vivo validation demonstrated that administration of adeno-associated virus-delivered PSAT1 short hairpin RNA or of a cell-penetrating itaconate antagonist significantly reduced tumour burden and prolonged survival. Our findings elucidate an unappreciated metabolic reprogramming axis in lung cancer bone metastases: macrophage-to-myofibroblast transition-derived itaconate alleviated cytoplasmic sequestration of ATF4 via HSPA8 ubiquitination, thereby activating its transcriptional target PSAT1. This mechanism converts immunometabolic byproducts into pro-tumorigenic signals that enhance bone metastasis. Notably, the HSPA8-ATF4-PSAT1 axis was identified as a key regulatory pathway governing metabolic reprogramming, thereby establishing a translational framework for targeting immunometabolic crosstalk in bone metastasis therapy.
    DOI:  https://doi.org/10.1038/s12276-026-01799-9
  34. Clin Immunol. 2026 Aug 01. pii: S1521-6616(26)00097-5. [Epub ahead of print]287 110759
    Fatty acid amide metabolism in systemic lupus erythematosus: Evidence, mechanisms, and translational potential.
    Jiawen Feng, Xuejia Zheng, Feng Zhu, Zhirui Gan, Zimeng Liu, Jingquan He, Yong Dai.
      Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease in which loss of immune tolerance, chronic inflammation, and metabolic reprogramming are closely interconnected. Fatty acid amides (FAAs) are endogenous lipid mediators that include N-acylethanolamines (NAEs), such as anandamide (AEA), palmitoylethanolamide (PEA), oleoylethanolamide (OEA), palmitoleoylethanolamide, and linoleoylethanolamide, as well as primary fatty acid amides such as palmitamide, octadecanamide, and oleamide. The evidence base for FAA metabolism in SLE should be interpreted at two levels. First, direct human multi-omics evidence now supports disease-associated alteration of several FAA-class serum metabolites: a serum proteome-metabolome study identified palmitoleoylethanolamide, linoleoylethanolamide, palmitamide, and octadecanamide among candidate metabolite biomarkers for SLE classification. Second, a targeted endocannabinoid study found increased 2-arachidonoylglycerol (2-AG) and enhanced diacylglycerol lipase (DAGL) activity in peripheral blood mononuclear cells, whereas AEA, PEA, and OEA were not significantly different from healthy controls. Because 2-AG is an endocannabinoid but not an FAA, these data support broader endocannabinoidome dysregulation rather than universal NAE dysregulation. Mechanistic evidence is primarily derived from lupus mouse models: PEA is reduced in serum and spleen of MRL/lpr mice and suppresses TLR9-induced IL-6 production, dendritic-cell and B-cell activation, IgM production, and B-cell proliferation; FAAH is upregulated in B cells from a lupus-prone Sle2z model and FAAH inhibition reduces receptor revision, RAG expression, and polyreactive autoantibody production; nano-encapsulated AEA reduces inflammatory cytokines and lesion severity in a murine model of cutaneous lupus erythematosus. Collectively, these findings indicate that FAA-related pathways are relevant to SLE, although current evidence remains heterogeneous, species-specific, and insufficient to establish causality in patients. Future work should combine targeted lipidomics, cell-type-resolved enzyme profiling, immune perturbation assays, and organ-specific phenotyping to determine whether FAA metabolism contributes to disease pathogenesis, biomarker development, or adjunctive therapy in defined SLE subsets.
    Keywords:  Anandamide; Endocannabinoidome; Fatty acid amide hydrolase; Fatty acid amides; Immunometabolism; N-acylethanolamines; Palmitoylethanolamide; Primary fatty acid amides; Systemic lupus erythematosus
    DOI:  https://doi.org/10.1016/j.clim.2026.110759
  35. Front Immunol. 2026 ;17 1865927
    Metabolic control of RNA methylation in rheumatoid arthritis: from synovial stress to pathogenic cellular adaptation.
    Shu Li, Lei Wan, Jin Yang, Kun Wang, Xiaojun Zhang, Xiaochuang Liu.
      Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent synovitis, invasive pannus formation, cartilage degradation, and bone erosion. Although metabolic reprogramming and epigenetic dysregulation are increasingly recognized as central features of rheumatoid arthritis, the mechanisms by which local metabolic stress is converted into durable pathogenic cellular states remain incompletely understood. Recent advances in epitranscriptomics suggest that dynamic RNA modifications, particularly RNA methylation, act as critical post-transcriptional regulators of immune and stromal cell adaptation. Local hypoxia, enhanced glycolytic flux, lactate accumulation, mitochondrial dysfunction, oxidative stress, and lipid metabolic imbalance collectively influence the expression, activity, substrate availability, and transcript selectivity of RNA methylation regulators. These metabolically conditioned RNA modification programs, including canonical N6-methyladenosine (m6A) and emerging non-m6A marks such as internal N7-methylguanosine (m7G), may help stabilize pathogenic phenotypes across multiple cell types. In fibroblast-like synoviocytes (FLS), RNA methylation sustains glycolytic fitness, invasive behavior, and resistance to apoptosis and ferroptosis. In macrophages, it reinforces inflammatory polarization and extracellular vesicle-mediated communication. In T cells and neutrophils, it contributes to Th17 skewing, defective autophagy, oxidative stress responses, and excessive neutrophil extracellular trap (NET) formation. We further discuss how RNA methylation integrates non-coding RNA networks, extracellular vesicle signaling, and regulated cell death pathways to maintain chronic synovial inflammation and tissue destruction. Finally, we highlight the translational implications of this metabolic-epitranscriptomic interface, including biomarker discovery, patient stratification, and microenvironment-informed therapeutic strategies. Targeting both metabolic stress and RNA methylation-dependent adaptation may provide new opportunities for precision-oriented intervention in rheumatoid arthritis.
    Keywords:  RNA methylation; cellular adaptation; cellular metabolism; epitranscriptomics; rheumatoid arthritis; synovial microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1865927
  36. Proc Natl Acad Sci U S A. 2026 Aug 11. 123(32): e2620143123
    A bacterial fatty acid enzyme hijacks nucleic acid-sensing Toll-like receptor signaling.
    William A Lathram, Priscilla C Lages, Christopher D Radka.
      Innate immune recognition shapes infection outcomes by linking microbial detection to host defense. Although pattern recognition receptors are classified by the ligands they detect (lipids, peptidoglycans, or nucleic acids) cross-talk between these pathways is increasingly recognized. Staphylococcus aureus, a major cause of skin and soft tissue infections, can persist intracellularly, evading immunity and antibiotics. Here, we describe a lipid-based immune evasion strategy in which the S. aureus enzyme oleate hydratase (OhyA) converts host fatty acids into hydroxylated lipids that antagonize TLR3-TRIF-IRF7 signaling, a pathway activated by double-stranded RNA. Deletion of ohyA unleashed this pathway, triggering rapid bacterial clearance, whereas loss of TLR3, TRIF, or IRF7 restored bacterial persistence, establishing a noncanonical antibacterial role for an antiviral signaling pathway. These findings identify a previously unrecognized interface between bacterial lipid metabolism and antiviral immune machinery, highlighting how pathogens manipulate cross-kingdom signaling to evade intracellular immunity.
    Keywords:  Staphylococcus aureus; acute-phase virulence; innate immunity; macrophages; oleate hydratase (OhyA)
    DOI:  https://doi.org/10.1073/pnas.2620143123
  37. PLoS Pathog. 2026 Aug 03. 22(8): e1013973
    RSAD2/VIPERIN and CMPK2 coordinate an immunometabolic response to Epstein-Barr Virus.
    Urvi S Zankharia, Adam M Glass, Wujuan Zhang, Qing Zhu, Janvhi Suresh Machhar, Ying Ye, Bhanu Chandra Karisetty, Jayamanna Wickramasinghe, Andrew Kossenkov, Jozef Madzo, Sun Sook Chung, Samantha S Soldan, R Jason Lamontagne, James M Wood, Lawrence D Harris, Tyler L Grove, Steven Jacobson, Aaron R Goldman, Chengyu Liang, Paul M Lieberman.
      Epstein-Barr Virus (EBV) infection and reactivation in B-lymphocytes are tightly regulated by host antiviral response genes. In the present study, we identify Interferon Stimulated Genes (ISGs) RSAD2 (radical S-adenosyl methionine domain-containing 2) and CMPK2 (Cytidine/Uridine Monophosphate Kinase 2) as key modulators of EBV expression and cellular response during EBV infection and reactivation. EBV primary infection and reactivation lead to a coordinated upregulation of RSAD2 and CMPK2. Depletion of RSAD2 reduced cell viability and limited EBV reactivation, while depletion of CMPK2 led to reactivation of EBV lytic gene expression during latency. Despite distinct subcellular localizations, RSAD2 at the endoplasmic reticulum (ER) and CMPK2 in the mitochondria, transcriptomic analysis revealed that both genes functionally converge and exhibit overlapping roles in driving shared immunometabolic pathways, specifically Interferon (IFN) signaling, MAPK signaling, oxidative phosphorylation, mitochondrial function, eukaryotic translation, and ATF-4-associated unfolded protein response (UPR). We show that RSAD2 and CMPK2 knockdown affects IRAK1-TRAF6-TAK1 expression levels, and RSAD2 overexpression downregulates NF-κB signaling by EBV membrane associated oncoprotein LMP1. Depletion of RSAD2 and CMPK2 had significant effects on global metabolites consistent with a remodeling of nucleotide metabolism, glycolysis, fatty acid biosynthesis and degradation of superoxides. EBV reactivation induced formation of antiviral ribonucleotide ddhCTP during lytic EBV reactivation which was strictly dependent on RSAD2. These observations demonstrate that RSAD2 and CMPK2 function in a coordinated ER-Mitochondria-Interferon signaling axis that shapes EBV reactivation and host immune control, including a novel layer of immunometabolic regulation modulating viral latency and reactivation.
    DOI:  https://doi.org/10.1371/journal.ppat.1013973
  38. Diabetes Obes Metab. 2026 Aug 02.
    Sodium Butyrate Attenuates Renal Fibrosis by Regulating Glycolysis and Histone H4K12 Lactylation in Diabetic Kidney Disease.
    Ping He, Mingxiu Wang, Hang Mei, Yue Liu, Min Wang, He Sun, Yali Peng, Xuan Ban, Yue Wang, Xiaofang Tang, Qiuling Fan.
       BACKGROUND: The role of histone lactylation in diabetes associated renal fibrosis remains poorly defined. In this study, we investigated the contribution of histone H4 lysine 12 lactylation (H4K12la) to abnormal glycolysis and renal fibrogenesis in diabetic kidney disease (DKD) and evaluated sodium butyrate (NaB) as a potential therapeutic modulator.
    METHODS: In this study, db/db mice (Bks. Cg-leprdb/leprdb) were employed as an in vivo model of DKD, and high glucose-treated human tubular epithelial cells (HK-2 cells) were used as an in vitro model to investigate whether NaB exerts protective effects on DKD via modulating glycolysis and histone H4K12 lactylation-mediated hypoxia-inducible factor-1α (HIF-1α) activation.
    RESULTS: We found that H4K12la expression was significantly increased in diabetic kidneys, which was closely associated with enhanced glycolysis related fibrosis. Analysis of kidney biopsy tissues from patients with DKD confirmed that H4K12la levels were significantly elevated. CUT&Tag sequencing in HK-2 cells revealed enrichment of H4K12la at genes involved in metabolic pathways, including the promoter region of HIF1A. In vivo and in vitro experiments demonstrated that NaB treatment suppressed the expression of glycolytic enzymes hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA), reduced lactate production, improved renal function, and attenuated kidney fibrosis under diabetic conditions. Mechanistically, these effects were associated with decreased H4K12la enrichment at the HIF1A promoter.
    CONCLUSIONS: Collectively, our findings identify aberrant renal glycolysis and H4K12la as key drivers of diabetic renal fibrosis and suggest that NaB mitigates fibrosis by modulating glycolysis-dependent H4K12la and HIF-1α signalling.
    Keywords:  diabetic kidney disease; glycolysis; histone H4 lysine 12 lactylation; hypoxia‐inducible factor‐1α; sodium butyrate
    DOI:  https://doi.org/10.1111/dom.71166
  39. Cell Insight. 2026 Oct;5(5): 100344
    Febrile-range temperature selectively limits sustained pDC-Derived IFN-α via attenuation of STAT1-Dependent feedback signaling.
    Yangyang Xu, Hao Yang, Lin Yang, Qing Zhang, Liang Cheng.
      Plasmacytoid dendritic cells (pDCs) are specialized sentinels of antiviral immunity and the dominant early source of interferon-α (IFN-α) during viral infection. While pDC-derived IFN-α restricts viral replication and provides a critical third signal for T cell activation, sustained type I interferon (IFN-I) signaling can drive immunopathology, and the physiological mechanisms that constrain this response remain incompletely understood. Here, we identify fever as a conserved host factor that selectively limits IFN-α production by pDCs. We show that febrile-range temperature does not impair early IFN-α induction but instead suppresses sustained IFN-α output in human and mouse pDCs. Mechanistically, elevated temperature attenuates signal transducer and activator of transcription 1 (STAT1) phosphorylation, thereby disrupting the IFN-I-dependent positive feedback loop required for IFN-I amplification following CpG-A stimulation. Pharmacological inhibition of protein phosphatase activity with okadaic acid (OA) restores STAT1 phosphorylation and rescues IFN-α production under febrile conditions. Together, these findings establish fever as a physiological regulator of pDC-derived IFN-I responses and reveal a temperature-dependent mechanism that constrains prolonged IFN-I production to prevent excessive immune activation.
    Keywords:  Febrile temperature; Interferon-α; STAT1 phosphorylation; pDC
    DOI:  https://doi.org/10.1016/j.cellin.2026.100344
  40. Int Immunopharmacol. 2026 Aug 07. pii: S1567-5769(26)01095-7. [Epub ahead of print]187 117249
    Targeting IMPDH2 by Casticin attenuates psoriatic inflammation by suppressing STAT3 activation in keratinocytes.
    Jia Guo, Qingyu Hong, Weina Li, Xiaoru Hu.
      Psoriasis is a chronic immune-mediated inflammatory disease. Inosine Monophosphate Dehydrogenase 2 (IMPDH2), the rate-limiting enzyme in de novo guanine nucleotide biosynthesis, is upregulated during cytokine-mediated inflammatory responses, yet its specific role in keratinocyte biology and psoriatic pathogenesis remains unexplored. Here, we identify IMPDH2 as a critical metabolic regulator of psoriatic inflammation. Integrated analysis of bulk and single-cell RNA sequencing datasets revealed consistent upregulation of IMPDH2 in psoriatic keratinocytes, which was further validated by immunofluorescence staining of patient skin biopsies. In an imiquimod (IMQ)-induced murine psoriasis model, pharmacological inhibition of IMPDH2 with Casticin attenuated disease progression and alleviated epidermal inflammation. Mechanistically, IMPDH2 promotes keratinocyte inflammation through GTP-dependent activation of STAT3 signaling: IMPDH2 knockdown or inhibition reduced STAT3 phosphorylation and suppressed inflammatory responses, effects that were reversed by exogenous GTP supplementation, whereas IMPDH2 overexpression enhanced STAT3 phosphorylation and inflammation. Supporting a direct causal link between IMPDH2 and STAT3, the STAT3 activator colivelin reversed the effect of IMPDH2 inhibition, while the STAT3 inhibitor Stattic abrogated the effect of IMPDH2 overexpression. Collectively, this study establishes a previously unrecognized IMPDH2-GTP-STAT3 axis driving keratinocyte inflammation and nominates Casticin as a promising therapeutic candidate for psoriasis.
    Keywords:  Casticin; IMPDH2; Keratinocyte; Psoriatic inflammation; STAT3; Stattic
    DOI:  https://doi.org/10.1016/j.intimp.2026.117249
  41. Glia. 2026 Oct;74(10): e70209
    Gq Signaling in Microglia Triggers Interferon Responses and Improves Outcome After Ischemic Stroke.
    Lynn Bitar, Marie-Luise Brehme, Charlotte Oldenburg, Sara Isla Cainzos, Michael G Kaul, Tobias Mummert, Malte Borggrewe, Thomas G Oertner, Tim Magnus.
      Post-stroke recovery remains limited despite advances in acute reperfusion therapies, underscoring the need to better understand underlying mechanisms that shape repair. Microglia, the resident immune cells of the central nervous system, orchestrate responses to ischemic injury and critically influence neurovascular remodeling, axonal reorganization, and functional recovery. Emerging evidence indicates that inflammatory preconditioning can reprogram microglial responses to subsequent insults, yet the exact intracellular signaling pathways mediating this adaptive state remain incompletely defined. Here, we used a chemogenetic approach to selectively activate Gq signaling in microglia employing a microglia-specific DREADD mouse model. This strategy mimics Gq-coupled receptor activation in microglia in the absence of peripheral immune engagement. Pre-ischemic Gq activation significantly reduced infarct sizes at 24 h after experimental stroke in female mice and at 7 days in both sexes. Morphological analyses revealed that Gq-conditioned microglia exhibited increased structural complexity, adopting a highly ramified, spatially compact phenotype and higher CD68 expression, indicating increased phagocytic activity. Transcriptional profiling demonstrated that Gq activation primes autophagy-related defense pathways in microglia, resulting in upregulation of interferon-stimulated genes 7 days after stroke in both sexes. Together, our findings identify Gq signaling as a key modulatory pathway capable of reprogramming microglial phenotype and enhancing stroke recovery. These results highlight the plasticity of microglial signaling networks and support targeted modulation of microglial Gq pathways.
    Keywords:  DREADD; interferon‐response; microglia; recovery phase; stroke
    DOI:  https://doi.org/10.1002/glia.70209
  42. Proc Natl Acad Sci U S A. 2026 Aug 11. 123(32): e2608715123
    Host inflammation-derived citrate enhances Salmonella Typhimurium pathogenesis by fueling growth and activating virulence.
    Hongmin Sun, Shuai Ma, Chenbo Kang, Mengjie Zhao, Jingnan Chen, Houliang Guo, Yiming Wang, Luoqing Feng, Lingyan Jiang, Bin Yang.
      Salmonella enterica serovar Typhimurium (STm) infection triggers robust intestinal inflammatory responses during host colonization. Although host inflammatory responses typically function as defense mechanisms, STm subverts these processes by co-opting inflammation-derived metabolites to increase both bacterial proliferation and intestinal colonization. Here, we demonstrate that STm-induced intestinal inflammation results in the significant accumulation of luminal citrate, which plays dual roles in STm pathogenesis, serving as both an anaerobic fermentation substrate to support bacterial growth and a virulence-activating signaling molecule. Mechanistically, the CitAB two-component system detects elevated citrate concentrations in the inflamed intestine, initiating the transcriptional activation of citrate fermentation genes to facilitate STm luminal proliferation. Moreover, CitAB-mediated citrate sensing directly upregulates hilD, which encodes the master regulator of Salmonella Pathogenicity Island 1, thereby enhancing type III secretion system-dependent epithelial invasion. Genetic disruption of either citrate anaerobic fermentation pathway or citrate-mediated virulence-regulating pathway severely compromises both intestinal colonization and invasive capacity of STm. These findings underscore citrate-responsive pathways as promising therapeutic targets for simultaneously disrupting STm metabolic adaptability and virulence.
    Keywords:  Salmonella pathogenesis; citrate fermentation; host–pathogen interaction; intestinal inflammation; virulence regulation
    DOI:  https://doi.org/10.1073/pnas.2608715123
  43. iScience. 2026 Aug 21. 29(8): 116940
    Fangchinoline drives NOS2-dependent host immunity to restrict intracellular enteric pathogens.
    Srikanth Sadhu, Rajdeep Dalal, Sonu Kumar Gupta, Yashwant Kumar, Deepak Kumar Rathore, Amit Awasthi.
      Intracellular bacterial infections remain difficult to treat due to antibiotic tolerance, immune evasion, and the emergence of multidrug resistance. Here, we identify Fangchinoline (Fcn), a natural alkaloid, as a host-directed immunomodulator that restricts intracellular Salmonella through NOS2-dependent nitric oxide (NO) signalling. Fcn enhances macrophage bactericidal activity and promotes Th1 immunity, leading to improved bacterial control in vitro and in vivo. Pharmacological inhibition of NO synthesis and loss of protection in NOS2-/- mice establish NO as a central effector mechanism. Serum metabolomics indicate Fcn is associated with immunometabolic changes consistent with enhanced NO biosynthesis. In addition, Fcn synergizes with suboptimal-dose Ciprofloxacin to control Salmonella infection while preserving host immune responses. Notably, Fcn primes memory-like T cell responses and enhances resistance upon subsequent infection. Collectively, these findings suggest Fangchinoline as a host-directed immunotherapeutic that integrates metabolic, innate, and adaptive immune programs to restrict intracellular enteric pathogens, including multidrug-resistant strains, and augment antibiotic efficacy.
    Keywords:  Antibiotic synergy; Fangchinoline; Host-directed therapy; MDR; NOS2; THP-1; Th1; Th17; Trained immunity
    DOI:  https://doi.org/10.1016/j.isci.2026.116940
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