bims-imicid 2026-02-01 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2026–02–01
thirty-six papers selected by
Dylan Gerard Ryan, Trinity College Dublin

Immunometabolic programming of macrophages in asthma pathogenesis and therapy.
Metabolic traits of T cells and the implications in autoimmune diseases.
The many facets of immunometabolism.
Lactate and lactylation in macrophage polarization of sepsis.
Tissue Immunometabolism in Autoimmunity.
Sepsis induces long-term reprogramming of human HSPCs and drives myeloid dysregulation in sepsis survivors.
Mitochondrial Dysfunction and Metabolic Reprogramming in Chronic Inflammatory Diseases: Molecular Insights and Therapeutic Opportunities.
Immune cell metabolic reprogramming in hepatocellular carcinoma: mechanisms, tumor microenvironment, and future immunotherapeutic directions.
Metabolic reprogramming of efferocytosis in the tumour microenvironment: From apoptotic-cell clearance to therapeutic targeting.
White spot syndrome virus IE1 protein hijacks the host pentose phosphate pathway to fuel viral replication.
S100A8 aggravates sepsis-associated encephalopathy by promoting PFKFB3-dependent glycolysis and microglial neuroinflammation.
Newcastle disease virus hijacks mitophagy to reprogram amino acid metabolism for enhanced replication.
Agmatine ameliorates poly(I:C)-induced lung injury through IL-10/STAT3-dependent reprogramming of macrophage inflammatory responses.
Butyrate-induced trained immunity enhances bacterial killing ability of head kidney macrophages in turbot (Scophthalmus maximus L.).
Polystyrene Nanoplastics Increase Macrophage Bactericidal Activity Through a Mechanism Involving Reactive Oxygen Species and Itaconate.
Mitochondrial DNA damage in HIV infection: a mechanistic driver of immunometabolic dysfunction and chronic inflammation.
CARM1-mediated hypoxanthine-enriched exosomes rewire inosine metabolism and impair CD8+ T cell antitumor function.
Obesity disrupts ILC2 metabolic and functional homeostasis by inhibiting mTORC1 signaling.
A type I interferon-mitochondrial axis regulates efferocytosis and interferon-stimulated gene induction in macrophages.
Long-Chain Fatty Acids Inhibit Myeloid-Derived Suppressor Cells to Delay Tumor Progression.
CAR Intrinsic Design Pre-Shapes Transcriptional and Metabolic Networks in CAR T Cells.
HMGCS2 desuccinylation modulates acetoacetate to drive tubule-macrophage inflammatory crosstalk in diabetic kidney disease.
NUDT7 Modulates the UBA52-SREBF1 Signaling Axis to Promote PRRSV Replication via Lipid Synthesis.
Western Diet Dampens T Regulatory Cell Function to Fuel Hepatic Inflammation in Metabolic Dysfunction-Associated Steatotic Liver Disease.
Kynurenine mediates the chemotherapy-induced intestinal toxicity through modulation of gut microbiota.
Enterococcus faecalis-derived lactic acid suppresses macrophage activation to facilitate persistent and polymicrobial wound infections.
Dietary fibre promotes chronic gut parasite infection via direct and time-dependent modulation of innate immunity.
Fasting-mimicking diet induces IFNβ secretion in tumor-associated macrophages via NRF1-mediated ubiquitin-dependent proteolysis of Trex1.
TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism.
Upregulation of the TCA Cycle and Oxidative Phosphorylation Enhances the Fitness of CD99 CAR-T Cells Under Dynamic Cultivation.
Leveraging glucan-induced trained immunity for the epigenetic and metabolic rewiring of macrophages to enhance colorectal cancer vaccine response.
Role of bile acid metabolites in regulating viral infections.
IL21-STAT3 controls the pentose phosphate pathway to support metabolic reprogramming and tumor progression in chronic lymphocytic leukemia.
PFKFB3 exacerbates myocardial injury by accelerating CXCR4hi neutrophil mobilization after acute myocardial infarction.
Nanobody Nb07 mitigates sepsis by blocking the PFKM-p53-PD-1 axis to enhance macrophage phagocytosis.
Epigenetic and metabolic reprogramming support plasma cell differentiation in germinal centers.

Front Physiol. 2025 ;16 1736340

Immunometabolic programming of macrophages in asthma pathogenesis and therapy.

Lisha Lu, Mengdi Shi, Wen Qin, Mingshu Yang, Xiaochang Wang, Youpeng Wang.

  Asthma is a heterogeneous chronic airway disease in which immune dysregulation and metabolic imbalance jointly shape inflammatory phenotypes and clinical outcomes. Growing evidence identifies pulmonary macrophages as central integrators of inflammatory cues and metabolic programs, linking acute exacerbations with long-term airway remodeling. Distinct tissue-resident and monocyte-derived macrophage subsets polarize along an M1-M2 spectrum and adopt glycolysis-dominated pro-inflammatory states or fatty acid oxidation-centered reparative states that differentially drive neutrophilic versus type 2-biased eosinophilic inflammation. Rewiring of arachidonic acid-derived eicosanoid synthesis and cholesterol handling further tailors macrophage effector functions and modulates responsiveness to glucocorticoids. Preclinical studies demonstrate that pharmacological manipulation of macrophage glucose and lipid metabolism can attenuate airway hyperresponsiveness and structural remodeling, highlighting immunometabolic circuits as promising therapeutic targets in asthma. This review summarizes current advances in macrophage ontogeny, polarization and metabolic reprogramming in the asthmatic lung. It also discusses how these insights may inform metabolism-focused, macrophage-directed interventions.

Keywords:  asthma; glycolysis; immunometabolism; lipid metabolism; macrophage

DOI:  https://doi.org/10.3389/fphys.2025.1736340
Autoimmun Rev. 2026 Jan 22. pii: S1568-9972(26)00003-0. [Epub ahead of print]25(2): 103989

Metabolic traits of T cells and the implications in autoimmune diseases.

Yi Zhou, Yuqi Zhou, Qing Zhu, Weinan Guo, Chunying Li.

  The metabolic activities of T cells play a pivotal role in regulating their activation, differentiation, and effector functions. In recent years, it has emerged as a key focus of research in the maintenance of immune homeostasis and the modulation of inflammatory responses. T cells not only rely on metabolic reprogramming to meet their energy and biosynthesis demands, but also utilize intermediate metabolites to regulate epigenetic modifications and then affect gene expression and cell fate. More importantly, T cell metabolism faces adaptive pressures in tissue-specific microenvironments, which impact their effector capabilities and participate in immune tolerance maintenance. Currently, traditional immunosuppressive therapy still has limitations in the treatment of autoimmune diseases, with notable side effects. Meanwhile, targeting T cell metabolism, as an emerging strategy for intervening in autoimmune responses, has demonstrated promising potential in multiple research studies. This review provides a comprehensive overview of the metabolic characteristics of T cells at different developmental stages and functional states, explores the interactive mechanisms between metabolism and epigenetic regulation in T cells, and discusses the influence of tissue microenvironments on T cell metabolic behavior. Finally, we highlighted recent advancements in targeting T cell metabolism for treating systemic lupus erythematosus, psoriasis, inflammatory bowel disease, and multiple sclerosis. This provides new directions for developing precise clinical intervention strategies for patients with autoimmune diseases.

Keywords:  Autoimmune diseases; Immunometabolism; Metabolism; T cells

DOI:  https://doi.org/10.1016/j.autrev.2026.103989
PLoS Biol. 2026 Jan;24(1): e3003641

The many facets of immunometabolism.

Joanna Clarke, Claudio Mauro.

Immunometabolism describes more than just metabolic shifts in immune cells. A new collection of articles shines a light on the many facets of immunometabolism, exploring the effects of molecular, cellular, and systemic metabolic mechanisms in health and disease.

DOI: https://doi.org/10.1371/journal.pbio.3003641
Front Cell Infect Microbiol. 2025 ;15 1662444

Lactate and lactylation in macrophage polarization of sepsis.

Jian Sun, Min Zhang, Li Zhang, Xinyue Zhang, Jingxiao Zhang.

  Sepsis, which is characterized by potentially fatal multiple organ dysfunction, is caused by an abnormal host response to a major infection. During sepsis, the pathogen stimulates the host to activate resistance mechanisms that enhance immune cells' oxygen consumption in inflammatory tissues and cells, and promote aerobic glycolysis. Lactate generated by aerobic glycolysis is an essential substrate for the tricarboxylic acid cycle and for post-translational modifications via histone lactylation and epigenetic regulation. It also serves as a signaling molecule that modulates macrophage polarization between pro- and anti-inflammatory phenotypes in response to inflammatory and metabolic signals in their local environment. The roles of lactate and lactylation modifications in cancer cell proliferation and invasion have been well studied and are now potential therapeutic targets for various malignancies. However, the roles of lactate and lactylation modification in sepsis remain unclear. This review focuses on lactate's regulatory mechanism and lactylation modification during macrophage polarization in sepsis, and investigates whether this regulation could be a potential therapeutic target for sepsis.

Keywords:  lactate; lactylation; macrophage polarization; metabolic reprogramming; sepsis

DOI:  https://doi.org/10.3389/fcimb.2025.1662444
Eur J Immunol. 2026 Jan;56(1): e70139

Tissue Immunometabolism in Autoimmunity.

Matteo Villa.

  Autoimmunity causes damage to organs targeted by the effector function of the immune response. The dynamics of autoimmunity in human peripheral tissues are not well understood due to the limited access to tissue samples. As cellular metabolism controls immune function, studying the crosstalk between the environment and cells within a tissue may provide information on how the metabolism of immune cells drives autoimmunity in peripheral tissues. In this review, I discuss some of the work that explored the complexity of the tissue environment, its sensing by cells in the tissue, and the consequences this has on cell and tissue functions, highlighting implications for autoimmune diseases. I also suggest a framework to study immunometabolism in tissues, contextualizing the metabolic choices of immune cells within the diversity of the extracellular environment they encounter.

Keywords:  immune function; immunometabolism; metabolic sensors; tissue environment

DOI:  https://doi.org/10.1002/eji.70139
J Inflamm (Lond). 2026 Jan 27.

Sepsis induces long-term reprogramming of human HSPCs and drives myeloid dysregulation in sepsis survivors.

Marco De Zuani, Petra Lázničková, Marcela Hortová Kohoutková, Veronika Bosáková, Ivana Andrejčinová, Natália Vadovičová, Veronika Tomášková, Alexandra Mýtniková, Julie Štíchová, Tomáš Tomáš, Jiří Hrdý, Kristýna Boráková, Stjepan Uldrijan, Marcela Vlková, Vladimír Šrámek, Martin Helán, Kamila Bendíčková, Jan Frič.

   BACKGROUND: Sepsis is a life-threatening condition characterised by an overwhelming immune response and high fatality. While most research has focused on its acute phase, many sepsis survivors remain immunologically weakened leaving them susceptible to serious complications from even mild infections. The mechanisms underlying this prolonged immune dysregulation remain unclear, limiting effective interventions. Here, we analysed whether sepsis induced long-term "training" in hematopoietic stem and progenitor cells (HSPCs), imprinting changes that persist in their myeloid progeny.
RESULTS: Peripheral blood analysis of 8 sepsis survivors, 12 patients with septic shock, and 10 healthy donors revealed a significant expansion of CD38 + progenitors in survivors, with increased megakaryocyte-erythroid progenitors and a near significant reduction in mature neutrophil counts. This shift suggests impaired granulopoiesis, favouring immature, immunosuppressive granulocytes. Differentiated macrophages from survivors' HSPCs exhibited impaired metabolic pathways after lipopolysaccharide stimulation, with downregulation of tricarboxylic acid cycle and glycolysis genes, indicating altered immune metabolism. Pathway analysis revealed enhanced type-I interferon (IFN) and JAK-STAT signalling in survivors' macrophages, reflective of potentially tolerance-prone reprogramming. Finally, exposing healthy donor HSPCs to IFNβ during macrophage differentiation reduced HSPC proliferation, increased apoptosis, and induced a metabolic shift towards glycolysis over mitochondrial respiration.
CONCLUSIONS: Together, these findings suggest that sepsis induces lasting reprogramming in HSPCs leading to myeloid progeny with altered immune memory that might drive immune dysregulation in survivors. These data open avenues to explore potential targets to better manage long-term immune alterations in sepsis survivors.

Keywords:  Dysregulation; Hematopoietic stem and progenitor cell; Macrophage; Metabolic impairment; Reprogramming; Sepsis; Sepsis survivor; Septic shock; Signalling

DOI:  https://doi.org/10.1186/s12950-025-00483-5
Curr Issues Mol Biol. 2025 Dec 14. pii: 1042. [Epub ahead of print]47(12):

Mitochondrial Dysfunction and Metabolic Reprogramming in Chronic Inflammatory Diseases: Molecular Insights and Therapeutic Opportunities.

Mi Eun Kim, Yeeun Lim, Jun Sik Lee.

  Chronic inflammatory diseases are driven by persistent immune activation and metabolic imbalance that disrupt tissue homeostasis. Mitochondrial dysfunction disrupts cellular bioenergetics and immune regulation, driving persistent inflammatory signaling. Mitochondrial dysfunction, characterized by excessive production of ROS, release of mitochondrial DNA, and defective mitophagy, amplifies inflammatory signaling and contributes to disease progression. Meanwhile, metabolic reprogramming in immune and stromal cells establishes distinct bioenergetic profiles. These profiles maintain either pro-inflammatory or anti-inflammatory phenotypes through key signaling regulators such as HIF-1α, AMPK, mTOR, and SIRT3. Crosstalk between mitochondrial and metabolic pathways determines whether inflammation persists or resolves. Recent advances have identified critical molecular regulators, including the NRF2-KEAP1 antioxidant system, the cGAS-STING innate immune pathway, and the PINK1-Parkin mitophagy pathway, as potential therapeutic targets. Pharmacologic modulation of metabolic checkpoints and restoration of mitochondrial homeostasis represent key strategies for re-establishing cellular homeostasis. Developing approaches, including NAD+ supplementation, mitochondrial transplantation, and gene-based interventions, also show significant therapeutic potential. This review provides a mechanistic synthesis of how mitochondrial dysfunction and metabolic reprogramming cooperate to maintain chronic inflammation and highlights molecular pathways that represent promising targets for precision therapeutics in inflammatory diseases.

Keywords:  chronic inflammation; immuno-metabolism; metabolic reprogramming; mitochondrial dysfunction; therapeutic targeting

DOI:  https://doi.org/10.3390/cimb47121042
Front Immunol. 2025 ;16 1697675

Immune cell metabolic reprogramming in hepatocellular carcinoma: mechanisms, tumor microenvironment, and future immunotherapeutic directions.

Lichen Zhou, Wenjie Zhang, Zhuoran Liu, Yaming Xie, Kangyi Jiang.

  Hepatocellular carcinoma (HCC), the most common primary liver cancer, continues to rank among the leading causes of cancer-related death despite improvements in early detection and systemic therapies. Therapeutic advances, including immune checkpoint blockade, cancer vaccines, and adoptive cell therapies, have broadened treatment possibilities. However, their efficacy and durability are often limited by immune evasion within a metabolically challenging tumor microenvironment (TME). This review consolidates current knowledge on how metabolic reprogramming in immune cells influences HCC progression, therapy resistance, and clinical outcomes. We discuss the roles of glycolysis, oxidative phosphorylation, fatty acid oxidation, and amino acid metabolism kynurenine pathways-in regulating the differentiation and function of T cells, regulatory T cells, macrophages, dendritic cells, natural killer cells, and B cells. Environmental factors such as hypoxia, lactate accumulation, adenosine signaling, and lipid remodeling act as key TME cues that suppress antigen presentation, impair cytotoxic responses, and promote immunosuppressive myeloid phenotypes. Building on these mechanisms, current strategies focus on targeting metabolic checkpoints in immune cells, reshaping the TME, and integrating metabolic modulation with checkpoint inhibitors to enhance therapeutic efficacy. In addition, candidate biomarkers (including circulating metabolites, multi-omics profiles, and liquid-biopsy indicators of immune metabolism) offer opportunities for patient stratification and dynamic monitoring. Together, these insights provide a conceptual framework in which precise modulation of immune metabolism can potentiate existing immunotherapies and guide rational combination strategies, warranting further clinical investigation to achieve sustained benefit in HCC.

Keywords:  hepatocellular carcinoma; immune cell metabolism; immunotherapy; metabolic reprogramming; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1697675
Clin Transl Med. 2026 Feb;16(2): e70601

Metabolic reprogramming of efferocytosis in the tumour microenvironment: From apoptotic-cell clearance to therapeutic targeting.

Qianlu Yang, Jie Yan, Qianxi Yang.

   BACKGROUND: Efferocytosis is a critical physiological process in which phagocytes clear apoptotic cells to maintain tissue homeostasis. However, within the tumour microenvironment (TME), this process is systematically hijacked by tumour cells, transforming it into a key pathological mechanism that drives immunosuppression, tumour progression and therapeutic resistance.
KEY FINDINGS: This review systematically elucidates the central role of metabolic reprogramming in this functional reversal, emphasising that efferocytosis is essentially an immunometabolic intersection process precisely regulated by metabolism. By releasing various metabolites such as ATP, lactate, adenosine and sphingosine-1-phosphate (S1P), apoptotic tumour cells not only recruit tumour-associated macrophages (TAMs) but also metabolically pre-program their functions, inducing polarisation towards a pro-tumourigenic M2-like phenotype. During the recognition stage, tumour cells exploit metabolic abnormalities, such as glycosylation and lipid oxidation, to modify surface 'eat-me/don't-eat-me' signals, thereby hijacking macrophage recognition and engulfment programs. Upon completion of engulfment, systemic reprogramming of amino acid, lipid and glucose metabolism occurs within macrophages. These metabolic alterations synergistically lock their immunosuppressive phenotype and establish a metabolic symbiosis between the tumour and stromal cells.
CONCLUSIONS: Based on these mechanisms, this review further explores translational strategies targeting the efferocytic-metabolic axis, aiming to reprogram the immunosuppressive efferocytosis into immune-activating events to overcome TME-mediated immunosuppression and enhance current therapeutic efficacy. By deeply dissecting the metabolic regulatory networks of efferocytosis, we aim to pave new directions for cancer immunotherapy, achieving a paradigm shift from 'metabolic hijacking' to 'metabolic interventional therapy'.

Keywords:  Cancer immunotherapy; Efferocytosis; Immunometabolism; Metabolic reprogramming; Tumour microenvironment (TME)

DOI:  https://doi.org/10.1002/ctm2.70601
PLoS Pathog. 2026 Jan 27. 22(1): e1013913

White spot syndrome virus IE1 protein hijacks the host pentose phosphate pathway to fuel viral replication.

Jia Zhang, Kaiyu Lu, Jinghua Zhu, Jude Juventus Aweya, Yueling Zhang, Defu Yao.

Viruses frequently reprogram host metabolism to support their replication. The pentose phosphate pathway (PPP), a key regulator of nucleotide synthesis and redox balance, is often targeted during infection. While PPP activation is well-known proviral mechanism in vertebrates, how this process occurs in invertebrate hosts remains unclear. Here, using the white spot syndrome virus (WSSV) and its penaeid shrimp host as a model, we identify a previously unrecognized viral strategy that directly reprograms the PPP through host-viral protein interaction. WSSV infection strongly induced the expression of key PPP enzymes, including glucose-6-phosphate dehydrogenase (G6PD) and transketolase-like 2 (TKTL2), and enhanced TKTL2 enzymatic activity. This activation increased the production of nicotinamide adenine dinucleotide phosphate (NADPH) and ribose-5-phosphate (R5P), two critical PPP metabolites. Functional assays confirmed that the PPP is essential for efficient WSSV replication, as knockdown or pharmacological inhibition of G6PD or TKTL2 significantly attenuated viral load and improved host survival. Mechanistically, the viral immediate-early protein IE1 was found to directly bind to the C-terminal region of TKTL2 (TKTL2-C1, residues 500-555), and enhance its enzymatic activity. This interaction promoted PPP flux, boosted NADPH and R5P biosynthesis, and suppressed reactive oxygen species (ROS) accumulation. Supplementation with NADPH, R5P, or a ROS scavenger restored viral replication defects caused by IE1 knockdown. Moreover, the IE1-binding fragment TKTL2-C1 acted as a competitive inhibitor that disrupted the IE1-TKTL2 interaction, decreased PPP flux, and reduced viral replication. Together, these findings demonstrate that WSSV IE1 directly activates host TKTL2 to rewire pentose phosphate metabolism, revealing a novel metabolic mechanism of viral pathogenesis and identifying the PPP as a potential target for antiviral intervention in aquaculture.

DOI: https://doi.org/10.1371/journal.ppat.1013913
Inflamm Res. 2026 Jan 27. 75(1): 21

S100A8 aggravates sepsis-associated encephalopathy by promoting PFKFB3-dependent glycolysis and microglial neuroinflammation.

Hongjie Hu, Shu Peng, Jingbo Chen, Dayong Li, Shuhui Wu, Hebin Jiang, Yuru Lu, Yaqin Song, Wei Zhu.

   BACKGROUND: Sepsis-associated encephalopathy (SAE) is a common and severe neurological complication of sepsis that markedly worsens long-term outcomes. Growing evidence suggest that metabolic reprogramming in microglia is a major driver of neuroinflammation in SAE; however, the molecular mechanisms that altered metabolism and inflammatory responses remain unclear.
METHODS: Transcriptomic data from public hippocampal datasets of SAE mice were analyzed to identify potential molecular drivers. We established a CLP-induced SAE model and performed AAV-mediated knockdown. For in vitro validation, BV2 microglia were treated with LPS to simulate neuroinflammation. Mechanistic validation was conducted using both genetic and pharmacological interventions. Cellular metabolism was examined through extracellular flux analysis and metabolite detection. Inflammatory responses were evaluated by cytokine profiling, and disease phenotypes were assessed using behavioral tests and histological analyses.
RESULTS: S100A8 was markedly upregulated in activated microglia during SAE. Its knockdown reduced microglial activation, protected hippocampal neurons, and improved cognitive performance. Transcriptomic profiling identified PFKFB3 as a downstream glycolytic target of S100A8. Mechanistically, S100A8 activated the PI3K/AKT/HIF-1α signaling cascade, thereby upregulating PFKFB3 and promoting glycolytic reprogramming and cytokine release. Functionally, S100A8 knockdown lowered lactate production and LDH activity, while reducing TNF-α, IL-6, and IL-1β secretion. Rescue experiments confirmed that PFKFB3 mediates the glycolytic and pro-inflammatory effects of S100A8.
CONCLUSIONS: This study demonstrates that S100A8 exacerbates SAE-related neuroinflammation and cognitive impairment by driving microglial metabolic reprogramming toward glycolysis via the PI3K/AKT/HIF-1α-PFKFB3 pathway. These findings highlight a mechanistic link between S100A8 and microglial metabolic reprogramming and neuroinflammation, and suggest that S100A8 could be a promising target for therapeutic intervention in SAE.

Keywords:  Glycolysis; Microglia; PFKFB3; S100A8; Sepsis-associated encephalopathy

DOI:  https://doi.org/10.1007/s00011-026-02183-z
Autophagy. 2026 Jan 29.

Newcastle disease virus hijacks mitophagy to reprogram amino acid metabolism for enhanced replication.

Yang Qu, Shanhui Ren, Ying Liao, Xusheng Qiu, Lei Tan, Cuiping Song, Yingjie Sun, Chan Ding.

  Mitochondria serve as the cellular "power plants," supplying energy and regulating metabolism, signal transduction, and other physiological processes. To successfully replicate within host cells, viruses have evolved multiple strategies to hijack mitochondrial functions. The oncolytic Newcastle disease virus (NDV) causes severe organelle damage in tumor cells; however, how it manipulates mitochondrial architecture to facilitate its own replication remains poorly understood. Here, we provide evidence that NDV infection disrupts mitochondrial spatial distribution and imbalances mitochondrial fusion and fission, leading to mitochondrial structural damage. The resulting accumulation of fragmented mitochondria is cleared via PRKN-dependent mitophagy, a process that supports NDV replication. Interestingly, although MAVS (mitochondrial antiviral signaling protein) is degraded along with mitophagy, genetic ablation of PRKN - while blocking MAVS degradation - does not restore downstream innate immune responses. This indicates that NDV exploits mitophagy to enhance replication through mechanisms not entirely dependent on the suppression of MAVS-mediated immunity. Given the central role of mitochondria, we further explored the link between amino acid metabolism and viral proliferation after NDV infection. Our results show that NDV-induced mitophagy leads to the accumulation of free amino acids in host cells, and this metabolic reprogramming promotes viral replication. In summary, we show that NDV drives its replication by remodeling mitochondrial dynamics to induce mitophagy, which in turn triggers an amino acid metabolic reprogramming that benefits the virus. This provides new insights into the mechanisms supporting efficient oncolytic NDV replication, offering potential avenues for therapeutic intervention in oncolytic virus therapy.

Keywords:  Amino acid metabolism; MAVS; NDV, PINK1-PRKN; mitochondrial dynamics; mitophagy

DOI:  https://doi.org/10.1080/15548627.2026.2624746
Int Immunopharmacol. 2026 Jan 23. pii: S1567-5769(26)00090-1. [Epub ahead of print]173 116247

Agmatine ameliorates poly(I:C)-induced lung injury through IL-10/STAT3-dependent reprogramming of macrophage inflammatory responses.

Zhen Sun, Xiaochang Zhang, Sha Liao, Zhe Zhou.

  The emerging field of immunometabolism posits that endogenous metabolites are pivotal regulators of immune responses, yet their therapeutic exploitation remains nascent. Investigating this paradigm in lung injury, we observed that agmatine, a decarboxylation product of L-arginine, was significantly depleted in poly(I:C)-induced murine lung injury and in a clinical cohort characterized by virus-associated pulmonary involvement, suggesting a potential association with lung pathology. In mice, exogenous agmatine supplementation ameliorated lung pathology and weight loss, effects that were contingent upon reprogramming of macrophage inflammatory responses. Mechanistically, agmatine exerts its anti-inflammatory effects through macrophage-specific mechanisms: it selectively inhibits macrophage-derived TNF-α and CXCL10 without affecting the NF-κB signaling pathway. Transcriptomic analysis of murine macrophages revealed that agmatine significantly upregulates IL-10 expression, and its protective effects were reversed using either IL-10R neutralizing antibody or macrophages from IL-10-deficient mice. In murine macrophages, further investigation confirmed that agmatine promotes STAT3 phosphorylation and nuclear translocation, while STAT3 knockdown partially abrogated its anti-inflammatory efficacy. Our findings position agmatine within the expanding realm of immunometabolic therapy, highlighting its potential as a therapeutic strategy for lung injury by harnessing an endogenous anti-inflammatory circuit.

Keywords:  Agmatine; IL-10/STAT3 signaling; Immunometabolism; Lung injury; Macrophage

DOI:  https://doi.org/10.1016/j.intimp.2026.116247
Fish Shellfish Immunol. 2026 Jan 27. pii: S1050-4648(26)00069-0. [Epub ahead of print] 111165

Butyrate-induced trained immunity enhances bacterial killing ability of head kidney macrophages in turbot (Scophthalmus maximus L.).

Shu Zhao, Jinjin Zhang, Wentao Wang, Shufei Liang, Mengqi Chen, Rui Shao, Xinmeng Liao, Qinghui Ai, Kangsen Mai, Min Wan.

  Trained immunity represents an evolutionarily conserved form of innate immune memory established through epigenetic and metabolic reprogramming. This study has demonstrated for the first time that butyrate, a key gut microbiota-derived metabolite, induces trained immunity in teleost macrophages. Our results revealed that priming head kidney macrophages (HKMs) from turbot (Scophthalmus maximus L.) with 1 μM of sodium butyrate (NaB) for 24 hours followed by a 5-day training period, established a durable memory phenotype of HKMs. Importantly, the bactericidal capacity against Edwardsiella tarda (E.tarda) infection was significantly enhanced in butyrate-trained HKMs, accompanied by the elevated pro-inflammatory response with significantly elevated expression of il1β and tnfα. Mechanistically, butyrate training activated the HIF-1α signaling pathway, modulated a late-phase metabolic shift towards anaerobic glycolysis and TCA cycle, evidenced by altered citrate metabolism and glutamine pathway activation. Furthermore, the gene expression of acly, acss1 and acss2 was increased, while the expression of acc1 was suppressed, leading to the increased acetyl-CoA pools. On the other hand, butyrate induced persistent epigenetic remodeling, evidenced by increased expression of histone acetyltransferase CBP/P300, HDAC3 suppression, and a robust accumulation of H3K27 acetylation. Remarkably, in vivo pretreatment with butyrate at a low dose conferred a 20% survival advantage against a lethal E. tarda challenge in juvenile turbot after 14 days post-exposure to butyrate compared to that in control group. These findings have established that butyrate drives innate immune memory in fish, offering novel insights and a promising candidate for prophylactic strategies against pathogenic infection in aquaculture.

Keywords:  Butyrate; Epigenetic modification; Macrophages; Metabolic reprogramming; Trained immunity; Turbot

DOI:  https://doi.org/10.1016/j.fsi.2026.111165
Nanomaterials (Basel). 2026 Jan 13. pii: 105. [Epub ahead of print]16(2):

Polystyrene Nanoplastics Increase Macrophage Bactericidal Activity Through a Mechanism Involving Reactive Oxygen Species and Itaconate.

Seyedeh Safoora Moosavi, Hamlet Acevedo Ospina, Albert Descoteaux.

  Nanoplastics are persistent environmental pollutants with potential risks to human health. Due to their small size, nanoplastics are internalized by macrophages, potentially altering their function. In this study we found that, in macrophages, 50 nm polystyrene nanoplastics were predominantly present in endosomes, lysosomes, and in the endoplasmic reticulum. Internalization of polystyrene nanoplastics increased the bactericidal activity of macrophages, which was inhibited by the NADPH oxidase inhibitor diphenyleneiodonium. Consistently, measurements of cellular and mitochondrial reactive oxygen species by flow cytometry revealed that polystyrene nanoplastics induced reactive oxygen species production in macrophages. In contrast, internalization of polystyrene nanoplastics reduced the levels of nitric oxide released by macrophages in response to E. coli. Internalization of polystyrene nanoplastics followed by the addition of E. coli induced high expression levels of the aconitate decarboxylase 1 gene. In the absence of this gene, killing of E. coli by macrophages exposed to polystyrene nanoplastics was significantly attenuated with respect to control macrophages, indicating a role for the mitochondrial metabolite itaconate in the increased bactericidal activity of macrophages exposed to polystyrene nanoplastics. Collectively, our results indicate that exposure of macrophages to polystyrene nanoplastics increases their bactericidal activity through the production of reactive oxygen species and of itaconate.

Keywords:  bactericidal activity; itaconate; macrophages; polystyrene nanoplastics; reactive oxygen species

DOI:  https://doi.org/10.3390/nano16020105
Front Immunol. 2025 ;16 1722463

Mitochondrial DNA damage in HIV infection: a mechanistic driver of immunometabolic dysfunction and chronic inflammation.

Li Ma, Xiaolei Wang, Huanbin Xu.

  Mitochondria are central regulators of cellular metabolism and immunity. Human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) are associated with metabolic complications and chronic inflammation, yet the underlying mechanisms remain incompletely understood. Increasing evidence implicates mitochondrial dysfunction-particularly mitochondrial DNA (mtDNA) damage-as a key contributor. HIV/SIV infection and ART both compromise mtDNA integrity through direct and indirect mechanisms, leading to impaired oxidative phosphorylation, dysregulated reactive oxygen species, and altered mitochondrial dynamics. These changes contribute to immune cell bioenergetic failure, T cell exhaustion, and cytosolic release of mtDNA, which can activate cGAS-STING and NLRP3 pathways to sustain chronic inflammation. In addition, certain ART drugs, especially early nucleoside reverse transcriptase inhibitors, inhibit polymerase γ, driving mtDNA depletion and mutation accumulation that underlie toxicities such as lipodystrophy, neuropathy, and accelerated aging. Monitoring mtDNA copy number and mutational burden may offer useful biomarkers of immune recovery and treatment-related complications. Targeting mitochondrial protection and repair represents a promising strategy to improve long-term outcomes in people living with HIV.

Keywords:  HIV; antiretroviral therapy; cGAS-STING; immunometabolism; inflammaging; mtDNA; oxidative stress

DOI:  https://doi.org/10.3389/fimmu.2025.1722463
Cell Death Differ. 2026 Jan 24.

CARM1-mediated hypoxanthine-enriched exosomes rewire inosine metabolism and impair CD8+ T cell antitumor function.

Jilong Yin, Zhipeng Su, Xi Hu, Haojie Sun, Zenghui Sun, Shuyu Zhou, Wenwen Xu, Ying Xi, Lanlan Liu, Jinwei Zhang, Qian Zhao, Yi Qiao, Jian Zhang, Yingjie Zhang, Ying Xu, Yuchen Fan, Xiaona You, Xiangbo Meng, Fabao Liu.

Cancer cells utilize tumor-derived exosomes to suppress antitumor immunity. Herein, we identify co-activator-associated arginine methyltransferase 1 (CARM1) as a key regulator of exosome biogenesis and metabolite sorting that inhibiting CD8+ T cell-mediated antitumor responses. Genetic ablation of CARM1 in breast cancer cells impairs immunosuppressive exosome secretion, enhancing CD8+ T cell infiltration, proliferation, and effector function. Mechanistically, CARM1 dimethylates apoptosis-linked gene-2 interacting protein X (ALIX) at arginine 757, facilitating its interaction with endosomal sorting complex required transport (ESCRT) components, and promoting tetraspanin-enriched exosome biogenesis. CARM1-dependent ALIX methylation enables selective packaging hypoxanthine into exosomes through direct binding to the ALIX F676 pocket. Exosomal hypoxanthine disrupts inosine metabolism in activated CD8+ T cells, inhibiting pentose phosphate pathway, glycolysis, nucleotide synthesis, and effector cytokine production. Co-administration of CARM1 inhibitor with inosine significantly enhances tumor-infiltrating CD8+ T cell cytotoxicity, reduces PD-1+TIM-3+ exhausted CD8+ T cells, and suppresses tumor growth. These findings establish the CARM1-ALIX-hypoxanthine axis as an immunosuppressive mechanism and suggest that combining CARM1 inhibition with inosine supplementation represent a promising therapeutic strategy for breast cancer.

DOI: https://doi.org/10.1038/s41418-026-01673-1
Cell Mol Immunol. 2026 Jan 27.

Obesity disrupts ILC2 metabolic and functional homeostasis by inhibiting mTORC1 signaling.

Lin Hu, Dongdi Wang, Yue Chen, Jinxin Qiu, Hongdong Wang, Youqin Zhang, Michelle Zhang, Xiaohui Su, Ju Qiu, Jiping Sun, Lei Shen.

  Group 2 innate lymphoid cells (ILC2s) play crucial roles in maintaining adipose tissue homeostasis. Recent studies indicate that ILC2s are dysregulated in obesity. However, the regulatory mechanisms governing adipose tissue ILC2 function remain inadequately explored. In this study, we demonstrated that mechanistic target of rapamycin complex 1 (mTORC1) activity is impaired in adipose tissue ILC2s from obese mice and humans. Deletion of Raptor, a critical adaptor protein in mTORC1, results in reduced numbers of ILC2s and diminished type 2 cytokine production in ILC2s, leading to increased adipose tissue inflammation and insulin resistance. Mechanistically, mTORC1 signaling upregulates PPARγ expression through HIF-1α, which promotes mitochondrial biogenesis and ST2 expression to sustain ILC2 metabolic and functional fitness. Together, our data identify mTORC1 as a crucial regulator that coordinates adipose tissue ILC2 metabolic and immunological homeostasis and prevents obesity-associated insulin resistance.

Keywords:  Group 2 innate lymphoid cells; PPARγ; ST2; mTORC1

DOI:  https://doi.org/10.1038/s41423-026-01389-9
Immunity. 2026 Jan 28. pii: S1074-7613(25)00566-7. [Epub ahead of print]

A type I interferon-mitochondrial axis regulates efferocytosis and interferon-stimulated gene induction in macrophages.

Gillian Dunphy, Irene Adán-Barrientos, Irene Fernández-Delgado, Carolina Villarroya-Beltri, Ignacio Heras-Murillo, Elena Moya-Ruiz, Miguel Sánchez-Álvarez, Aitor Jarit-Cabanillas, Miguel A Del Pozo, Susana Guerra, Francisco Sánchez-Madrid, David Sancho.

  Macrophage metabolism is intricately linked to cellular function. Contrasting with Toll-like receptor (TLR) stimulation, cytosolic nucleic acid sensing induced a decrease in mitochondrial membrane potential (MMP) while maintaining mitochondrial respiration. Interferon α/β (IFN-I) receptor (IFNAR) signaling was necessary and sufficient for this metabolic response. IFNAR signaling induced interferon-stimulated gene 15 (ISG15) expression and ISGylation of mitochondrial proteins, including subunits of mitochondrial complex V, increasing ATP production and decreasing MMP, thus enhancing macrophage efferocytic capacity. Moreover, the IFNAR-ISG15-mediated drop in MMP activated the mitochondrial protease OMA1, inducing mitochondrial fission and decreasing endoplasmic reticulum-mitochondria communication, thus dampening IFN-stimulated gene (ISG) induction. Loss of ISG15 or OMA1 enhanced histone acetylation and ISG induction upon IFN-I stimulation, in a manner dependent on mitochondrial calcium uptake. This increase in ISG induction provided protection against acute viral infections. These data indicate that IFNAR-ISG15 signaling boosts efferocytosis while limiting ISG induction, thereby promoting the resolution of inflammation.

Keywords:  efferocytosis; interferon-stimulated genes; macrophage; metabolism; mitochondrial endoplasmic reticulum contacts; mitochondrial fission; mitochondrial membrane potential; oxidative phosphorylation; type I interferon; viral infection

DOI:  https://doi.org/10.1016/j.immuni.2025.12.010
Curr Issues Mol Biol. 2026 Jan 22. pii: 118. [Epub ahead of print]48(1):

Long-Chain Fatty Acids Inhibit Myeloid-Derived Suppressor Cells to Delay Tumor Progression.

Xinyu Liu, Fanni Kong, Zhangyuzi Deng, Jing Yang, Ying Cao, Hongjie Chen.

  It is broadly realized that the body's metabolism has a profound impact on tumor progression. However, pathophysiological mechanisms underlying the metabolic modulation of the tumor immune microenvironment remain incompletely understood. Here, we report that long-chain fatty acids (LCFAs) can directly modulate the function of myeloid-derived suppressor cells (MDSCs), a central component of establishing the tumor immune microenvironment. In vitro or in vivo exposure to LCFAs significantly reduces the expression levels of signature immunosuppressive genes of both monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs). As a result, mice fed with a diet of high LCFA content exhibit delayed tumor progression and prolonged survival in different cancer models. Furthermore, this LCFA-mediated inhibition of M-MDSCs and PMN-MDSCs correlates with enhanced CD8+ T antitumor immunity, which is abolished in tumor-bearing nude mice. These results have revealed a previously under-recognized role of LCFAs in the tumor immune microenvironment, implicating novel therapeutic strategies for cancer treatment.

Keywords:  antitumor immunity; long-chain fatty acids (LCFAs); myeloid-derived suppressor cells (MDSCs); tumor immune microenvironment

DOI:  https://doi.org/10.3390/cimb48010118
Metabolites. 2026 Jan 07. pii: 52. [Epub ahead of print]16(1):

CAR Intrinsic Design Pre-Shapes Transcriptional and Metabolic Networks in CAR T Cells.

Didem Agac Cobanoglu, Samantha Franklin, Yue Hu, Devon J Boland, Xiaotong Song.

   BACKGROUND/OBJECTIVES: Chimeric antigen receptor (CAR) T cells are a powerful cancer therapy, but their function depends heavily on internal signaling domains and metabolic adaptability. Most studies evaluate CAR behavior upon antigen exposure, yet intrinsic signaling properties may pre-program CAR T cell states even in the absence of stimulation. This study investigates how CAR design and metabolic support shape baseline transcriptional programs, focusing on tonic signaling and NF-κB-related pathways.
METHODS: We engineered CAR T cells targeting HER2 or GPC3 antigens, incorporating either 4-1BB or CD28 co-stimulatory domains, respectively. A subset of cells was further modified with adenosine deaminase 1 (ADA1) and CD26 to degrade extracellular adenosine and supply inosine, a metabolic strategy termed metabolic refueling (MR). Bulk RNA-seq was performed on resting T cells without antigen stimulation. We analyzed differential gene expression, gene set enrichment (GO, KEGG, Hallmarks), and transcription factor activity (DoRothEA) to assess the impact of CAR design and MR on T cell programming.
RESULTS: All CAR T cells exhibited activation of NF-κB-centered inflammatory programs at baseline, indicating tonic signaling. GPC3 CAR T cells showed stronger baseline activation than HER2 CAR T cells. Metabolic refueling amplified these programs without altering their directionality, enhancing inflammatory, survival, and effector modules. Transcription factor activity scores mirrored these trends, highlighting RELA, FOS, and STATs as key regulatory nodes.
CONCLUSIONS: CAR-intrinsic features, notably co-stimulatory domain choice, define the tonic NF-κB activation tone in resting CAR T cells. Metabolic refueling boosts these baseline states without overstimulation, suggesting it may be especially valuable for weaker CAR constructs. These findings provide a framework for tuning CAR T cell function through combinatorial design strategies targeting signaling and metabolism.

Keywords:  NF-kB; RNA-seq; chimeric antigen receptors; transcription

DOI:  https://doi.org/10.3390/metabo16010052
Metabolism. 2026 Jan 22. pii: S0026-0495(26)00019-3. [Epub ahead of print]177 156510

HMGCS2 desuccinylation modulates acetoacetate to drive tubule-macrophage inflammatory crosstalk in diabetic kidney disease.

Ziyue Lin, Dan Lv, He Zha, Handeng Liu, Rui Peng, Jiakun Yang, Wuchao Li, Xiaohui Liao, Yan Sun, Zheng Zhang.

  Mitochondrial dysfunction in renal tubular epithelial cells (TECs) is a hallmark of diabetic kidney disease (DKD), accompanied by macrophage infiltration, yet how metabolic perturbations in TECs-macrophage driven inflammation remains unclear. Here, we identify 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), the rate-limiting enzyme of ketogenesis, as a critical mediator linking tubular mitochondrial stress to macrophage M1 polarization in DKD. In mice subjected to DKD, conditional knockout HMGCS2 in TECs decreases mitochondrial fission of TECs, M1 macrophage infiltration and tubular inflammatory injury. Combining LC-MS/MS and ketone flux detection reveals that desuccinylated HMGCS2 produced more acetoacetate (AcAc) than beta-hydroxybutyrate (β-HB) in TECs of DKD. Mechanistically, Signal Transducer and Activator of Transcription 3 (STAT3) promotes Hmgcs2 transcription and sirtuin 5 (SIRT5) activates HMGCS2 through lysine desuccinylation at K367, which promotes AcAc overload shuttling from TECs to macrophages. AcAc acts as a signaling metabolite to activate the MIF/ERK pathway, driving M1 polarization and amplifying a pro-inflammatory feedback loop of tubular injury. In addition, AAV9-mediated Hmgcs2 silencing therapy improves tubular inflammatory injury and attenuates DKD progression. Taken together, this study unveils a tubule-macrophage metabolic crosstalk axis mediated by HMGCS2-driven AcAc accumulation, which couples mitochondrial stress to immune response in DKD.

Keywords:  Acetoacetate; Diabetic kidney disease; HMGCS2; Macrophage infiltration; Mitochondrial damage

DOI:  https://doi.org/10.1016/j.metabol.2026.156510
Int J Biol Sci. 2026 ;22(3): 1590-1610

NUDT7 Modulates the UBA52-SREBF1 Signaling Axis to Promote PRRSV Replication via Lipid Synthesis.

Yuchao Yan, Changyan Li, Junyang Zhang, Ruiqiao Li, Boxuan Yin, Sicheng Zhang, Yinhao Zhang, Xinyi Zhang, Jun Han, Jinhai Huang.

  Identifying cellular proteins and processes crucial for viral infection is vital for comprehending virus-induced disease mechanisms and developing host-targeted therapies. PRRSV has been shown to take advantage of host metabolic reprogramming and immunosuppression to promote virus production, but the host factors that coordinate these processes have not been fully elucidated. Here, we showed that NUDT7 expression was significantly increased during PRRSV infection by ETS1 targeting its promoter. We also found NUDT7 enhance PRRSV replication by reprograms viral infection-induced intracellular lipid droplets (LDs) synthesis. Mechanistically, NUDT7 interacts with and targets the ubiquitin-ribosomal fusion protein UBA52 for proteasomal degradation. NUDT7 enhances lipid droplet formation and stabilizes the lipogenic transcription factor SREBF1 by blocking UBA52-mediated K11/K27/K48 polyubiquitination. NUDT7-UBA52-SREBF1 axis drives lipid metabolic reprogramming, creating a favorable environment for PRRSV replication. Additionally, NUDT7 inhibits type I interferon signaling and the expression of interferon-stimulated genes, facilitating viral immune evasion. These findings suggest that NUDT7 could be a therapeutic target for combating PRRSV infection, offering a novel perspective and theoretical foundation for developing targeted metabolic-immune antiviral strategies.

Keywords:  NUDT7; PRRSV; innate immunity; lipid metabolism; ubiquitin

DOI:  https://doi.org/10.7150/ijbs.127844
Cells. 2026 Jan 16. pii: 165. [Epub ahead of print]15(2):

Western Diet Dampens T Regulatory Cell Function to Fuel Hepatic Inflammation in Metabolic Dysfunction-Associated Steatotic Liver Disease.

Sudrishti Chaudhary, Ravi Rai, Pabitra B Pal, Dana Tedesco, Daniel Rossmiller, Biki Gupta, Aatur D Singhi, Satdarshan P Monga, Arash Grakoui, Smita S Iyer, Reben Raeman.

  The immunosuppressive T regulatory cells (Tregs) regulate immune responses and maintain immune homeostasis, yet their functions in metabolic dysfunction-associated steatotic liver disease (MASLD) remain controversial. Here we report increased accumulation of Tregs and effector T cells within the liver parenchyma of mice fed a Western diet (WD). This pattern was also observed in MASH patients, where an increase in intrahepatic Tregs was noted. In the absence of adaptive immune cells in Rag1 KO mice, WD promoted accumulation of intrahepatic neutrophils and macrophages and exacerbated hepatic inflammation and fibrosis. Similarly, targeted Treg depletion exacerbated WD-induced hepatic inflammation and fibrosis. In Treg-depleted mice, hepatic injury was associated with increased accumulation of neutrophils, macrophages, and activated T cells in the liver. Conversely, induction of Treg numbers using recombinant IL2/αIL2 mAb cocktail reduced hepatic steatosis, inflammation, and fibrosis in WD-fed mice. Analysis of intrahepatic Tregs from WD-fed mice revealed a phenotypic signature of impaired Treg function in MASLD. Ex vivo functional studies showed that glucose and palmitate, but not fructose, impaired the immunosuppressive ability of Treg cells. The findings indicate that the liver microenvironment in MASLD impairs the ability of Tregs to suppress effector immune cell activation, thus perpetuating chronic inflammation and driving MASLD progression.

Keywords:  MASH; MASLD; T regulatory cells; fibrosis; inflammation

DOI:  https://doi.org/10.3390/cells15020165
Nat Commun. 2026 Jan 27.

Kynurenine mediates the chemotherapy-induced intestinal toxicity through modulation of gut microbiota.

Hongyu Xie, Jingyi Yang, Jinjie Wu, Wenhao Ma, Haoyang Xu, Shuang Guo, Yanchun Xie, Zhanhao Luo, Dayi Liang, Mujia Cao, Danling Liu, Sanqing Jin, Ping Lan, Zhen He.

Chemotherapy-induced intestinal toxicity is a major dose-limiting complication, but the underlying mechanisms linking systemic metabolism to localized gut damage are poorly understood. Here we show that serum L-kynurenine, a tryptophan metabolite, is elevated in patients with severe oxaliplatin-induced intestinal toxicity. Accumulation of L-kynurenine is driven by IFNγ-mediated induction of indoleamine 2,3-dioxygenase 1 (IDO1) in myeloid cells. Using scRNA-seq and myeloid cell-specific knockout models, we confirm that myeloid cell-derived L-kynurenine exacerbates toxicity. Critically, L-kynurenine accumulation drives gut dysbiosis, characterized by the loss of Lactobacillus johnsonii, and subsequently activates the TNFα/JNK pathway, leading to intestinal epithelial apoptosis. Pharmacological inhibition or engineered reduction of L-kynurenine mitigates chemotherapy-induced intestinal injury. Our findings reveal an important role of L-kynurenine from myeloid cells in chemotherapy tolerance and propose its targeting as a potential therapeutic strategy.

DOI: https://doi.org/10.1038/s41467-026-68741-5
Cell Host Microbe. 2026 Jan 27. pii: S1931-3128(26)00002-8. [Epub ahead of print]

Enterococcus faecalis-derived lactic acid suppresses macrophage activation to facilitate persistent and polymicrobial wound infections.

Ronni A G da Silva, Brenda Yin Qi Tien, Patrick Hsien Neng Kao, Haris Antypas, Cenk Celik, Ai Zhu Casandra Tan, Muhammad Hafiz Ismail, Guangan Hu, Kelvin Kian Long Chong, Guillaume Thibault, Jianzhu Chen, Kimberly A Kline.

  Macrophage activation is essential for innate immunity and antimicrobial defense. We show that Enterococcus faecalis suppresses macrophage activation through lactic-acid-mediated acidification of the extracellular environment, enabling pathogen persistence. E. faecalis-derived lactic acid acts via the lactate transporter monocarboxylate transporter 1 (MCT-1) and the sensor GPR81 to initiate complementary mechanisms that collaboratively reduce nuclear factor κB (NF-κB) activity. Lactic acid acts through MCT-1 to inhibit extracellular signal-regulated kinase and STAT3 phosphorylation, leading to reduced levels of the adaptor MyD88 involved in NF-κB activation. Lactic acid signaling to GPR81 induces phosphorylation of the transcription factor YAP, ultimately attenuating NF-κB signaling. A bacterial mutant lacking lactate dehydrogenase is unable to acidify the environment and thus fails to inhibit NF-κB. In a murine wound infection model, lactic-acid-driven immunosuppression enables prolonged E. faecalis persistence and enhances the fitness of co-infecting bacteria such as Escherichia coli. These findings reveal how bacterial lactic acid subverts innate immunity to support chronic and polymicrobial infections.

Keywords:  E. faecalis; NF-κB inhibition; lactic acid; lactic acid signaling; lactic-acid-mediated immune evasion; macrophage immunosuppression; macrophages; polymicrobial wound infections; recalcitrant wound infections

DOI:  https://doi.org/10.1016/j.chom.2026.01.002
Microbiome. 2026 Jan 26.

Dietary fibre promotes chronic gut parasite infection via direct and time-dependent modulation of innate immunity.

Laura J Myhill, Penille Jensen, Pankaj Arora, Anne M Jensen, Ling Zhu, Amalie Vedsted-Jakobsen, Eiríkur A Thormar, Alexandra von Münchow, Mahesha M Poojary, Marianne N Lund, Stig M Thamsborg, Morten T Limborg, Benjamin A H Jensen, Andrew R Williams.

BACKGROUND: Dietary fibre is an important regulator of the gut microbiome and is associated with many health benefits. However, high levels of fibre intake have also been reported to exacerbate some diseases.
RESULTS: Here, we show that mice fed semi-synthetic diets supplemented with purified inulin fibre develop chronic infections with the parasitic whipworm Trichuris muris, concomitant with dysregulated innate antimicrobial defences, exacerbated mucosal inflammation, and altered tryptophan metabolism. Inhibition of tryptophan catabolism or neutralizing either IL-27 or IL-18 restored infection resistance. Inulin-fed mice developed gut microbiota dysbiosis during parasite infection, with Proteobacteria becoming dominant. However, despite drastic differences in gut microbiota compositions in control- and inulin-fed mice, microbiota transfer and depletion experiments demonstrated that dietary inulin triggered chronic T. muris infection in a microbiota-independent manner. Importantly, removing inulin from the diet within a critical immune development window rapidly restored anti-parasite immunity, indicating direct, time-dependent modulation of mucosal immune responses.
CONCLUSIONS: These data reveal T. muris-induced dysbiosis as a consequence rather than a causative factor of diet-driven changes in host susceptibility, and establish a direct link between dietary fibre and host defence at mucosal surfaces. Video Abstract.

DOI: https://doi.org/10.1186/s40168-025-02333-1
Br J Cancer. 2026 Jan 29.

Fasting-mimicking diet induces IFNβ secretion in tumor-associated macrophages via NRF1-mediated ubiquitin-dependent proteolysis of Trex1.

Jiakun Li, Wenjiao Jiang, Guowei Tu, Ziwen Zhong, Zhe Luo, Tiffany Horng, Changhong Miao.

BACKGROUND: Fasting-mimicking diet (FMD) is a safe and effective strategy in clinical oncology via metabolically restricting tumour growth and remodelling the immunity. To date, few studies have investigated the impact of on tumour-associated macrophages (TAMs), which are a crucial component of immune cells in the tumour microenvironment. Fasting can induce the ubiquitin-proteasome system (UPS) to regulate intracellular protein turnover homoeostasis, while Nuclear Factor Erythroid 2-like 1 (NRF1; encoded by the gene Nfe2l1), which controls proteasome gene transcription, may potentially be induced by fasting. However, whether NRF1 is induced by FMD/fasting, and how NRF1-mediated protein turnover works on TAMs remain unknown. This study investigated the hypothesis that FMD activates the anti-tumour immunity of TAMs by ubiquitinated protein metabolism.
METHODS: Subcutaneous MC38 tumour models were established in WT and myeloid-specific NRF1 knockout (Mye-NFE2L1-/-) C57BL/6 mice, treated with FMD alone or combined with intraperitoneal Trex1 inhibitor (Trex1-IN-1). TAMs were isolated from tumour tissues using CD11b+ magnetic bead sorting. In vitro, bone marrow-derived macrophages (BMDMs) were co-cultured with MC38 in fasting medium, with MC38 proliferation assessed by CCK8 assay. BMDM-derived TAMs (B-TAMs) were induced by MC38 supernatant under fasting conditions. IFNβ levels in serum and cell supernatant were measured by ELISA. RNA-seq was performed to compare WT and Mye-NFE2L1-/- BMDMs under fasting conditions. Protein levels of cGAS-Sting pathway components, ubiquitinated proteins, and nuclear NRF1 were analysed by Western blot, while Trex1 ubiquitination was assessed by Co-IP. qPCR quantified IFNβ-related gene expression and mitochondrial DNA (mtDNA) copy number. Trex1-mitochondria colocalization was examined by immunofluorescence, and Trex1-bound mtDNA levels were determined by ChIP-qPCR.
RESULTS: FMD/fasting triggers interferon-β (IFNβ) secretion in TAMs, which is driven by protein metabolism. In TAMs with FMD, an initial accumulation of ubiquitinated proteins occurs concomitantly with the induction of NRF1 in response to fasting-induced energy stress, leading to the ubiquitin/proteasome-dependent proteolysis of the three prime repair exonuclease 1 (Trex1) through UPS. Such a process engages type I interferon responses, which derepress the cGAS-Sting-IFNβ axis to promote anti-tumour effects of TAMs. In the absence of NRF1, Trex1 accumulates due to impaired UPS and binds to mtDNA, disrupting cGAS sensing of mtDNA to inhibit IFNβ secretion in TAMs, which attenuates anti-tumour effects of FMD/fasting.
CONCLUSION: In this study, we revealed for the first time that FMD/fasting coordinates NRF1-UPS and Trex1/Sting-mediated type I interferon responses in TAMs that contribute to suppressing tumour growth. Graphical abstract: FMD upregulates the entry of NRF1 into the TAM nucleus to promote gene expression of proteasome subunits, which induces the ubiquitin/proteasome-dependent proteolysis of Trex1, leading to derepression of the cGAS-Sting-IFNβ axis. On the other hand, FMD triggers increasing of mtDNA in TAMs, promoting the cGAS-Sting-IFNβ axis to release IFNβ. In myeloid NRF1 knockout TAMs, transcriptional levels of proteasome subunits are reduced, resulting in impaired proteolysis of Trex1 and its subsequent accumulation during fasting. Then, Trex1 binds to mtDNA, directing the inhibition of the cGAS-Sting-IFNβ axis and inhibiting IFNβ secretion of macrophages.

DOI: https://doi.org/10.1038/s41416-025-03319-4
Nat Commun. 2026 Jan 24.

TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism.

Astrid F Feiten, Kilian Dahm, Kai Schlepckow, Bettina van Lengerich, Jung H Suh, Anika Reifschneider, Benedikt Wefers, Laura M Bartos, Karin Wind-Mark, Lis de Weerd, Thomas Ulas, Elena De-Domenico, Pia Grundschöttel, Stefan Paulusch, Benjamin Tast, Tamisa Honda, Stephan A Müller, Matthias Becker, Igor Khalin, Alessio Ricci, Arthur Liesz, Bettina Brunner, Claudia Krenner, Katrin Buschmann, Brigitte Nuscher, Lena Spieth, Niklas Junker, Stefan A Berghoff, Sonnet S Davis, Jonas J Neher, Wolfgang Wurst, Nikolaus Plesnila, Joseph W Lewcock, Mikael Simons, Stefan F Lichtenthaler, Gilbert Di Paolo, Matthias Brendel, Anja Capell, Kathryn M Monroe, Joachim L Schultze, Christian Haass.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a central regulator of microglial activity and loss-of-function coding variants are major risk factors for late onset Alzheimer's disease (LOAD). To better understand the molecular and functional changes associated with TREM2 signalling in microglia, we generated a TREM2 reporter mouse. In APP transgenic animals, bulk RNA-sequencing of isolated microglia sorted based on reporter expression highlighted TREM2 level-related changes in major immunometabolic pathways, and enrichment of genes in oxidative phosphorylation and cholesterol metabolism in microglia with increased TREM2 expression. Metabolic and lipidomic profiling of sorted microglia showed that, independent of Aβ pathology, TREM2 expression correlated with signatures consistent with increased cellular redox, energetics, and cholesterol homoeostasis. In accordance, metabolic activity correlated with phagocytic capacity. Finally, we performed chronic treatment with a TREM2 agonist antibody and identified a window of TREM2 expression where microglia are most responsive, thereby informing clinical applications of TREM2 agonists.

DOI: https://doi.org/10.1038/s41467-026-68706-8
Int J Mol Sci. 2026 Jan 07. pii: 607. [Epub ahead of print]27(2):

Upregulation of the TCA Cycle and Oxidative Phosphorylation Enhances the Fitness of CD99 CAR-T Cells Under Dynamic Cultivation.

Jiaxuan Zhao, Youyong Wang, Yixuan Wang, Ge Dong, Han Wu, Yeting Cui, Lixing Gu, Fenfang Zhao, Guanlin Zhao, Jinyu Kang, Qian Zhang, Nan Liu, Ning Wang, Xiao Sun, Yao Xu, Tongcun Zhang, Jiangzhou Shi.

  The manufacturing process contributes significantly to the proliferation, metabolic state, and functional persistence of chimeric antigen receptor (CAR)-T cells. However, how different culture systems regulate CAR-T cell metabolism and thereby influence their long-term antitumor activity remains poorly understood. In this study, we compared dynamic cultivation using a wave bioreactor with static expansion systems (gas-permeable and conventional T-flasks) for the production of CD99-specific CAR-T cells. CAR-T cells expanded by the wave bioreactor exhibited faster proliferation and stronger cytotoxicity during culture. Upon repeated antigen stimulation, they retained these enhanced functional properties and showed the reduced expression of immune checkpoint molecules, preferentially preserved memory-like subsets, and displayed transcriptional features consistent with memory maintenance and exhaustion resistance. Targeted metabolomic profiling revealed enhanced Tricarboxylic Acid (TCA) cycle activity and features consistent with sustained oxidative phosphorylation, supporting mitochondrial-centered metabolic reprogramming. In a Ewing sarcoma xenograft model, wave bioreactor-cultured CAR-T cells showed a greater percentage of memory-like tumor-infiltrating lymphocytes. Collectively, these results indicate that wave bioreactor-based dynamic cultivation promotes mitochondrial metabolic reprogramming, which is characterized by an enhanced TCA cycle and sustained oxidative phosphorylation, thereby sustaining CAR-T cell functionality and providing a robust platform for the manufacturing of potent and durable cellular therapeutics.

Keywords:  CD99; TCA cycle; chimeric antigen receptor T cells; dynamic cultivation; functional persistence; oxidative phosphorylation

DOI:  https://doi.org/10.3390/ijms27020607
Nat Commun. 2026 Jan 28.

Leveraging glucan-induced trained immunity for the epigenetic and metabolic rewiring of macrophages to enhance colorectal cancer vaccine response.

Firas Hamdan, Sara Gandolfi, Federica D'Alessio, Yvonne Giannoula, Julia Kolikova, Manlio Fusciello, Elisa Zaghen, Alessandra Napolano, Salvatore Russo, Ozan Izci, Paolo Bottega, Jacopo Chiaro, Kirsi-Marja Alanen, Gabriella Antignani, Michaela Feodoroff, Virpi Stigzelius, Milda Sakalauskaite, Janita Sandberg, Anni I Nieminen, Nicola Zambrano, Ove Eriksson, Satu Mustjoki, Toni T Seppälä, Mikaela Grönholm, Vincenzo Cerullo.

Colorectal cancer (CRC) remains refractory to most immunotherapies, with cancer vaccines failing due to an immunosuppressive tumor microenvironment. Here, we show that β-glucan-induced trained immunity overcomes these barriers by reprogramming macrophages through H3K4me3-dependent epigenetic modifications and metabolic rewiring. In female mice vaccinated with peptide-coated adenovirus-based vaccine PeptiCrad, training enhances glycolysis with creatine metabolism sustaining CXCL9/10 production, enabling macrophages to recruit NK cells via CXCR3. In turn, NK cells produce CCL5, driving cDC1 infiltration and antigen presentation, which together amplify effector memory CD8⁺ T cell responses. Moreover, with human peripheral blood mononuclear cells and CRC patient-derived organoids, trained macrophages boost NK migration, antigen-specific T cell activation, and tumor killing. These findings highlight trained immunity as a powerful adjuvant to reinvigorate colorectal cancer vaccination.

DOI: https://doi.org/10.1038/s41467-026-68466-5
Trends Microbiol. 2026 Jan 27. pii: S0966-842X(25)00371-3. [Epub ahead of print]

Role of bile acid metabolites in regulating viral infections.

Yanan Zhang, Shu Jeffrey Zhu.

  Gut microbiota-derived bile acids are emerging as pivotal regulators of viral pathogenesis. They exhibit dual roles by directly blocking or promoting viral entry, while also systemically tuning immune responses. This forum discusses how spatiotemporal mapping of these interactions can address unresolved questions and inspire novel microbiome-based antiviral strategies.

Keywords:  bile acid metabolism; gut microbiota; immunomodulation; pathogenesis; viral infection

DOI:  https://doi.org/10.1016/j.tim.2025.12.008
Hemasphere. 2026 Jan;10(1): e70292

IL21-STAT3 controls the pentose phosphate pathway to support metabolic reprogramming and tumor progression in chronic lymphocytic leukemia.

Rosita Del Prete, Vjola Tusha, Helga Simon-Molas, Virginia Anna Gazziero, Federica Nardi, Roberta Drago, Gaia Bartolini, Danilo Licastro, Margherita Malchiodi, Cristina Mariottini, Giuseppe Marotta, Giulio Caravagna, Stefano Bruscoli, Eric Eldering, Alessandro Gozzetti, Monica Bocchia, Anna Kabanova.

Studying how microenvironmental cues influence metabolic reprogramming can uncover mechanisms driving tumor progression. Using an in vitro model with proliferative stimuli of the in vivo lymph node niche (LN)-including interleukin-21 (IL-21)-we examined metabolic rewiring in chronic lymphocytic leukemia (CLL) cells. We found that the metabolic intermediates of upper glycolysis and its branching pathways are key in fulfilling metabolic demands of proliferating CLL cells. Among branching pathways, the pentose phosphate pathway (PPP) was the most transcriptionally upregulated in proliferating CLL cells. Increased expression of PPP genes was detected ex vivo at the bulk and single-cell level in the LN-resident and -emigrating CLL cells, with more consistency across enzymes of the nonoxidative PPP branch. Expression of the latter correlated with shorter failure-free survival in CLL patients. At the cellular level, metabolomics and 13C-glucose tracing confirmed high activity of the non-oxidative PPP in proliferating CLL cells. IL-21 regulated the expression of PPP enzymes, with STAT3 serving as the primary downstream effector. CRISPR/Cas9-mediated silencing of PPP enzymes revealed that, in vitro, proliferating CLL cells from most patients were not dependent on these enzymes. In contrast, silencing transketolase (TKT)-the rate-limiting enzyme of the non-oxidative PPP-abolished tumor engraftment in vivo, demonstrating that CLL cells rely on this pathway within the tumor microenvironment. These findings uncover a CLL-specific metabolic reprogramming wherein IL-21-STAT3 drives PPP activity and identify the nonoxidative PPP as a critical in vivo vulnerability of leukemic cells in the murine CLL model.

DOI: https://doi.org/10.1002/hem3.70292
PLoS One. 2026 ;21(1): e0333657

PFKFB3 exacerbates myocardial injury by accelerating CXCR4hi neutrophil mobilization after acute myocardial infarction.

Yingjia Xu, Min Xiao, Qin Zhu, Wutao Wang, Danrui Wang, Dadong Liu, Zongying Yu.

BACKGROUND: CXCR4hi neutrophil mobilization is a key cause of myocardial damage after acute myocardial infarction (AMI). 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a key glycolytic enzyme, plays a crucial role in regulating neutrophil function. However, researchers have not clearly determined whether PFKFB3 is involved in AMI-induced CXCR4hi neutrophil mobilization.
METHODS: First, the circulating CXCR4hi neutrophil percentage and neutrophil Pfkfb3 mRNA expression were measured in AMI patients and left anterior descending coronary artery (LADCA)-ligated mice. Next, we explored the relationship between PFKFB3 and CXCR4 expression in lipopolysaccharide (LPS)-stimulated cell models. Neu-PFKFB3-/- mice were used to investigate the effect of conditional knockout of the Pfkfb3 gene in neutrophils on AMI-induced myocardial inflammatory injury.
RESULTS: In AMI patients, the expression level of Pfkfb3 gene was markedly regulated in AMI-induced neutrophils and was positively related to the content of plasma inflammatory factors in AMI patients. Further study revealed that PFKFB3 promotes CXCR4hi neutrophil mobilization by reprogramming glycolytic metabolism and subsequently exacerbates inflammatory injury in the myocardial tissues of AMI model mice. However, specific knockout of Pfkfb3 gene in neutrophils protects mice from AMI-induced myocardial inflammatory injury by inhibiting the mobilization of CXCR4hi neutrophils.
CONCLUSIONS: PFKFB3 exacerbates AMI-induced myocardial inflammatory injury by accelerating CXCR4hi neutrophil mobilization. The mechanism involves PFKFB3-mediated reprogramming of glycolytic metabolism.

DOI: https://doi.org/10.1371/journal.pone.0333657
Theranostics. 2026 ;16(7): 3408-3425

Nanobody Nb07 mitigates sepsis by blocking the PFKM-p53-PD-1 axis to enhance macrophage phagocytosis.

Binbin Ji, Hui Guo, Rong Xing, Miaomiao Sun, Yu Cheng, Chen Yao, Hanyong Zhu, Xuerong Wang, Ruihan Jiang, Xin Chen, Zimeng Liu, Suyan Wang, Fei Xu, Fangyu Zhang, Fuxing Dong, Xiucheng Pan, Jing Yang, Yuchen Pan.

  Rationale: Macrophage phagocytosis is essential for pathogen clearance during sepsis. We previously demonstrated that the glycolytic enzyme 6-phosphofructokinase, muscle type (PFKM), modulates macrophage functions and its deficiency alleviates sepsis in mice. However, the function of PFKM in regulating macrophage phagocytosis remains unclear. Methods: CD14+ monocytes were sorted by flow cytometry from healthy volunteers and septic patients, and the subcellular localization of PFKM was assessed by immunofluorescence. Nuclear translocation mechanisms and PFKM-p53 interaction were identified by Co-immunoprecipitation coupled with mass spectrometry (Co-IP/MS) and validated by Co-IP. Transcriptomic sequencing was used to identify the downstream target of the PFKM-p53 complex. Inflammatory cytokine levels were detected by ELISA and real-time RT-PCR, and the phagocytosis of macrophages was assessed by flow cytometry. Dual-luciferase reporter assays and ChIP were employed to investigate whether PFKM acts as a co-regulator of p53 in mediating Pdcd1 transcription. Nanobodies targeting PFKM-p53 were screened and subsequently synthesized according to the sequences. The effect of nuclear PFKM and the therapeutic effect of nanobodies were evaluated on the well-established sepsis mouse models induced by Escherichia coli or cecal ligation and puncture. Results: PFKM translocated to the macrophage nucleus during sepsis. Nuclear accumulation of PFKM impaired phagocytosis through a non-glycolytic "moonlighting" function and exacerbated sepsis. Mechanistically, PFKM interacts with p53, which facilitates its nuclear translocation. Subsequently, PFKM promotes p53 acetylation at K120, enhancing p53 binding to the Pdcd1 promoter and driving its transcription, thereby suppressing macrophage phagocytosis. Blocking the PFKM-p53 interaction with a nanobody, Nb07, restored phagocytosis of macrophages and alleviated sepsis in mice. Conclusion: Our data reveal the PFKM-p53-PD-1 axis that suppresses macrophage phagocytosis in sepsis and highlight the therapeutic potential of targeting this pathway with nanobody-based strategies.

Keywords:  PFKM; macrophage; moonlighting function; phagocytosis; sepsis

DOI:  https://doi.org/10.7150/thno.124303
J Exp Med. 2026 Mar 02. pii: e20250569. [Epub ahead of print]223(3):

Epigenetic and metabolic reprogramming support plasma cell differentiation in germinal centers.

Yuliang Wang, Xinyi Yang, Mengting Lou, Tiantian Chen, Wen Li, Cuifang Yang, Le Zhang, Zhenming Cai, Yuren Fan, Sulan Zhai, Shengze Zhang, Yunli Wang, Xiaoming Wang, Jingjing Chen.

The germinal center (GC) is a specialized structure that ensures the production of high-quality antibodies. Although recent studies have pinpointed the existence of a pre-plasma cell (prePC) population within mouse GC B cells, it remains unclear how these prePCs mechanistically differentiate into PCs. Additionally, there is a lack of validation of these findings in human cells. Here, we demonstrate CD205 is highly expressed in prePCs both in mouse and in human. The histone H3 lysine 27 demethylase Kdm6b, not Kdm6a, potently enhances the differentiation of prePCs into bona fide PCs by removing repressive H3K27me3 marks at the Irf4 locus. Interestingly, prePCs favor glutamine metabolism, which provides α-ketoglutarate as a substrate for the demethylation reaction of Kdm6b. Thus, prePCs require metabolic and epigenetic reprogramming to differentiate into PCs in the GC.

DOI: https://doi.org/10.1084/jem.20250569