bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–10–11
forty-two papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Mycoplasma gallisepticum uses itaconate-associated mitochondrial inhibition to suppress host immunometabolism.
  2. Immunometabolic programming of macrophages and tumor-associated macrophages: metabolic pathways shaping polarization, immune regulation, and disease outcomes.
  3. Metabolic reprogramming of pathogenic CD4+ T helper cells attenuates inflammatory bowel disease in mice.
  4. A guide to B cell metabolism.
  5. Supraphysiological Citrate Exposure Drives Nonmonotonic Immunometabolic Reprogramming and Proinflammatory Activation in Monocytes/Macrophages.
  6. HIF-1α-driven lactate from mesenchymal stem/stromal cells reprograms monocyte metabolism and suppresses autoimmune uveoretinitis.
  7. Spatiotemporal heterogeneity and dynamic evolution of microglial glucose metabolic reprogramming in Alzheimer's disease.
  8. Boosting CAR T cell efficacy in cancer with metabolic insights from design to diet.
  9. 4-Octyl itaconate suppresses IFN-γ-induced MHC II expression in bone marrow-derived macrophages.
  10. Salmonella typhimurium exploits macrophage-derived arginine as an intracellular signal for SPI-2 virulence gene activation.
  11. Immunometabolic Reprogramming in the Bone Marrow Niche: Mechanisms, Plasticity, and Precision Therapeutic Targeting.
  12. Integrated Metabolomic and Bioenergetic Profiling Reveals Axl as a Key Regulator of Macrophage Homeostasis.
  13. Immunometabolic alterations in post-traumatic stress disorder.
  14. Glutamine metabolism keeps pathogenic hepatic CD4+ T cells in check.
  15. Context-dependent roles of ketone metabolism in intestinal inflammation.
  16. L-Arginine inhibits NLRP3 inflammasome activation.
  17. Microbiota-derived metabolic priming of CAR-T cell fitness: a translational framework for next-generation cell therapy.
  18. Sodium-Glucose Cotransporter SGLT2 Supports Metabolic Fitness and Ferroptosis Resistance in CAR-T Cells to Enhance Activity Against Solid Tumors.
  19. Histone lactylation: a metabolic-epigenetic bridge linking glycolysis to salivary gland fibrosis in Sjögren's disease.
  20. Coordinated nicotinamide metabolism by NAMPT and NNMT: Integrating metabolic, epigenetic and immune crosstalk.
  21. Monosodium urate induces macrophage M1 polarization and endothelial apoptosis via the HIF1A-glycolysis axis.
  22. Cebpb/JAK2/STAT3 signaling pathway mediated M1 macrophage polarization and metabolic rewiring drive COPD pathogenesis.
  23. Non-enzymatic protein modifications at the interface of metabolism and immunity.
  24. MINDY1 drives metabolic-immune crosstalk via OGT-UGP2-UDPG axis to promote immunosuppressive macrophage reprogramming.
  25. Cancer competition for vitamin B2 creates metabolic checkpoint for T cell ferroptosis.
  26. Deoxysphingolipids activate cGAS-STING and enhance antitumor immunity.
  27. Fatty acid-dependent cidality in Mycobacterium avium and Mycobacterium abscessus: intracellular acidification by itaconic acid.
  28. The immunometabolic tipping point: forecasting the systemic shift from psoriasis to psoriatic arthritis.
  29. Mitochondrial metabolic dysfunction in airway epithelial cells promotes goblet cell metaplasia and more severe asthma.
  30. Cell jamming transition is regulated by mitochondrial pyruvate transport and endocytosis.
  31. Trajectories in immunometabolism.
  32. D-Mannose treats obesity by increasing adipose Treg cells and suppressing gut Firmicutes.
  33. VARS2 deficiency drives seronegative myasthenia gravis pathology via mitochondrial, immune, and neuromuscular dysregulation.
  34. Programmed cell death protein 1 (PD-1) regulates metabolic activity of regulatory T cells in ischemia-induced acute kidney injury.
  35. Iron-Metabolism-Modulating Carbon Dots Controllably Orchestrates Antibacterial and Immunoregulatory Synergy for Effective Bacterial Sepsis Therapy.
  36. Palmitate puts ACLY in shape to reprogram macrophages.
  37. The Role of Sodium in Th17/Treg Immune Dysregulation and Autoimmunity.
  38. Metabolic reprogramming, macrophage polarization, and intercellular crosstalk in pelvic inflammatory disease: emerging paradigms and therapeutic opportunities.
  39. Differential formation of nitrate-responsive mycobacterial intracytoplasmic membranes during Mycobacterium tuberculosis infection.
  40. Mitochondrial pyruvate carrier inhibition restrains germinal center T follicular helper cells attenuating chronic graft-versus-host disease.
  41. An MMP12-Enriched Kupffer Cell-Associated Programme Links ATF3-Associated Immunometabolic Remodeling to Hepatic Metabolic Dysfunction and Fibrotic Communication Networks.
  42. HDAC3-driven immunometabolic reprogramming in type 2 diabetes and its complications: from enzymatic deacetylation to non-enzymatic scaffolding.
  1. bioRxiv. 2026 Aug 14. pii: 2026.08.12.744485. [Epub ahead of print]
    Mycoplasma gallisepticum uses itaconate-associated mitochondrial inhibition to suppress host immunometabolism.
    Soren Z Coulson, Reihane Eric, Chidambaram Ramanathan, Katie M Talbott, Francis E Tillman, Anna Perez-Umphrey, Truc Chi Thi Pham, Paul S Simone, Brandt D Pence, James S Adelman, Yufeng Zhang.
      Many pathogens actively suppress early host immune responses to enhance their fitness. Mitochondria function as key regulators of immune activation, yet whether pathogens suppress host immunity by manipulating mitochondrial metabolism in vivo remains largely unknown. During an innate immune response, the metabolite itaconate increases in abundance and acts as an immunomodulator, due to its inhibition of succinate dehydrogenase (SDH), a key mitochondrial regulator of cellular immunity. We hypothesized that Mycoplasma gallisepticum (MG), a recently emerged pathogen of wild songbirds, most notably house finches ( Haemorhous mexicanus ), suppresses early host immune responses by limiting SDH-dependent immune activation via itaconate. We tested these hypotheses using experimental 3-day infection of finches with heat-killed MG, live MG or pharmacological elevation of the SDH inhibitor itaconate. Following inoculation, we quantified intracellular itaconate and mitochondrial respiratory function in peripheral blood mononuclear cells (PBMCs) and pro-inflammatory cytokine gene expression in erythrocytes, in addition to infected tissues (trachea and conjunctiva). Heat-killed MG increased SDH-dependent mitochondrial respiration in PBMCs and cytokine gene expression in erythrocytes, but live MG did not show these increases, but revealed increased itaconate accumulation in PBMCs. Dimethyl itaconate administration reproduced the suppressed metabolic and immune phenotype in blood cells observed with live MG, suggesting an itaconate-associated mechanism. In contrast, live MG increased mitochondrial respiration and gene expression levels of cytokines in eyelid conjunctiva, whereas other treatments did not. These findings indicate that MG suppresses host metabolic and cytokine signaling in systemically circulating immune cells through a mechanism consistent with itaconate-mediated inhibition of SDH-dependent mitochondrial respiration, while still inducing an inflammatory response at the site of infection. Our data suggest that MG, like other pathogens, can commandeer host immunometabolic pathways during infection to their benefit and that mitochondria are a key site of competition between host and pathogen.
    DOI:  https://doi.org/10.64898/2026.08.12.744485
  2. Front Immunol. 2026 ;17 1803827
    Immunometabolic programming of macrophages and tumor-associated macrophages: metabolic pathways shaping polarization, immune regulation, and disease outcomes.
    Jiawei He, Bowen Wang, Enze Lei, Ningfeng Mao.
      Macrophages adapt to hanging tissue environments by rewiring cellular metabolism, and these metabolic programs actively instruct immune functions rather than merely supplying energy. Across health and disease, shifts in glycolysis, mitochondrial oxidative phosphorylation, lipid handling, and amino acid utilization shape macrophage polarization, inflammatory mediator production, antigen presentation, and interactions with lymphocytes. In tumors, these principles are illustrated by tumor-associated macrophages (TAMs), which are reprogrammed by hypoxia, nutrient competition, and tumor-derived metabolites to adopt phenotypes that frequently support immune evasion, angiogenesis, extracellular matrix remodeling, and therapy resistance. This review integrates core macrophage immunometabolic pathways with TAM biology, emphasizing how lactate accumulation, altered lipid mediators, cholesterol remodeling, and amino acid dependencies reshape macrophage states and suppress antitumor immunity through checkpoint signaling and metabolic deprivation. We also discuss how immunometabolism intersects with regulated cell death, highlighting ferroptosis as an emerging mechanism linking iron metabolism, lipid peroxidation, redox control, and immune outcomes. Finally, we summarize therapeutic opportunities targeting metabolic nodes in tumor cells and macrophages, including modulation of lactate transport, fatty acid oxidation and synthesis, arginine/tryptophan pathways, and PI3Kγ-linked programs, and consider how interspecies differences between murine and human macrophages influence translational interpretation. Together, these insights position macrophage immunometabolism as a tractable framework for designing interventions that reshape immune responses in cancer and other macrophage-driven diseases.
    Keywords:  ferroptosis; glycolysis and oxidative phosphorylation; lipid metabolism; macrophage immunometabolism; metabolic reprogramming; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2026.1803827
  3. Sci Signal. 2026 Oct 06. 19(958): eaeb2392
    Metabolic reprogramming of pathogenic CD4+ T helper cells attenuates inflammatory bowel disease in mice.
    Shravan K Mishra, Leena M Abdelrahman, Hyun Se Kim Lee, Lucía Valenzuela-Pérez, Dina F Manna, Tanner J Abram, Lama Mohamed Ali, Heidi M Davidson, Omar M Hassan, William A Faubion, Petra Hirsova, Adebowale O Bamidele.
      CD4+ effector T helper 1 (TH1) cells drive inflammatory bowel disease (IBD). Here, we investigated how integrated signaling, metabolic, and epigenetic programs sustain their pathogenic persistence. We found that enforcing mitochondrial pyruvate metabolism with methyl pyruvate (MePyr) suppressed TH1 cell effector function and induced the acquisition of a regulatory-like phenotype. MePyr suppressed the activity of glycogen synthase kinase 3β (GSK3β), promoting a metabolic shift from glycolysis toward oxidative phosphorylation (OXPHOS) and limiting the accumulation of intracellular acetyl-CoA. This metabolic reprogramming decreased histone H3 acetylation at genes encoding inflammatory cytokines, thereby decreasing TH1 cell-associated gene expression. Restoration of inflammatory cytokine production by acetate supplementation or histone deacetylase inhibition established acetyl-CoA-dependent histone acetylation as a mechanistic link between metabolic flux and effector function. Conversely, the cytokine interleukin-21 enhanced TH1 cell effector activity by promoting a GSK3β-dependent shift from OXPHOS to glycolysis. Single-cell transcriptomic analysis of Crohn's disease tissue revealed enrichment of glycolytic gene programs in nonregulatory CD4+ T cells. Consistent with these findings, pharmacologic inhibition of GSK3β attenuated disease severity in a T cell-transfer mouse model of colitis. Together, these findings identify a GSK3β-dependent metabolic-epigenetic axis that sustains TH1 cell pathogenicity and highlight GSK3β as a potential therapeutic target for IBD.
    DOI:  https://doi.org/10.1126/scisignal.aeb2392
  4. Nat Rev Immunol. 2026 Oct 07.
    A guide to B cell metabolism.
    Yavuz F Yazicioglu, Glenn R Bantug, Christoph Hess, Alexander J Clarke.
      The metabolism of immune cells must adapt dynamically to support their diverse functions. B cells, which are the key cellular mediators of humoral immunity, undergo extensive metabolic changes throughout their development and function, starting from their commitment to the B cell lineage in the bone marrow. In the periphery, further rounds of metabolic adaptation in B cells are driven by temporally regulated changes in signalling cues, energetic demands and nutrient availability within specialized tissue niches. Although they have historically been less well studied than other immune cell types, emerging evidence shows that B cells deploy mechanistically distinct metabolic strategies that are tightly linked to their effector identity. Recognizing B cell metabolism as its own biological entity is, therefore, crucial to the study of humoral immune responses. In this Review, we examine the metabolic pathways that regulate B cell homeostasis, their integration with cell signalling networks, and their adaptation to the metabolic environment across spatial and temporal scales. We further discuss how aberrations in these pathways can contribute to B cell-driven malignancies, autoimmunity, inborn errors of immunity, and B cell-tropic infections. We position B cell metabolism as a rapidly expanding frontier within immunometabolism in both health and disease.
    DOI:  https://doi.org/10.1038/s41577-026-01355-6
  5. FASEB J. 2026 Oct 15. 40(19): e72326
    Supraphysiological Citrate Exposure Drives Nonmonotonic Immunometabolic Reprogramming and Proinflammatory Activation in Monocytes/Macrophages.
    Xiaoyan Gu, Yinghui Lu, Lu Wang, Di Nan, Chunxia Zheng, Dehua Gong.
      Patients receiving continuous renal replacement therapy (CRRT) with regional citrate anticoagulation (RCA) frequently experience systemic citrate accumulation, yet its immunometabolic consequences remain poorly understood. Here, we examined how supraphysiological citrate shapes macrophage inflammatory responses using isotope tracing, targeted metabolomics, and in vitro and in vivo inflammatory models. In LPS-stimulated THP-1 cells, U-13C-citrate was preferentially retained in proximal citrate-associated metabolite pools, with robust labeling of citrate, cis-aconitate, and itaconate, but minimal labeling of downstream tricarboxylic acid (TCA)-related or glycolytic intermediates. Citrate exposure also increased proximal citrate-related metabolite pools, while acetyl-CoA levels were more strongly increased at 1 mM than at 6 mM. U-13C-glucose tracing further showed that citrate exposure redistributed glucose-derived carbon, increasing its retention in glycolysis- and pentose phosphate pathway-related intermediates while reducing its relative contribution to proximal TCA-related metabolites. Consistent with this, citrate increased extracellular acidification rate and upregulated GLUT1 and PKM2. In THP-1 cells, PBMCs, and BMDMs, citrate amplified LPS-induced cytokine production in a nonmonotonic manner, with 1 mM generally producing a stronger proinflammatory effect than 6 mM. In vivo, citrate administration exacerbated hypercytokinemia and increased M1 macrophage polarization in LPS-treated mice. Moreover, citrate-induced proinflammatory responses were attenuated by inhibition of glycolysis, citrate-to-acetyl-CoA conversion, or histone acetylation. Collectively, supraphysiological citrate promotes monocyte/macrophage proinflammatory activation through metabolic and epigenetic reprogramming, with a nonlinear dose response. These findings suggest that systemic citrate accumulation during CRRT may aggravate inflammatory tissue or organ injury and should be considered carefully in inflammatory settings.
    Keywords:  CRRT; citrate accumulation; histone acetylation; metabolic reprogramming; proinflammatory response
    DOI:  https://doi.org/10.1096/fj.202601873RR
  6. Cell Rep. 2026 Oct 07. pii: S2211-1247(26)01183-6. [Epub ahead of print]45(10): 118104
    HIF-1α-driven lactate from mesenchymal stem/stromal cells reprograms monocyte metabolism and suppresses autoimmune uveoretinitis.
    Hyun Ju Lee, Jung Hwa Ko, Jin Suk Ryu, Joo Youn Oh.
      Metabolic reprogramming of immune cells is emerging as a therapeutic strategy for autoimmune diseases. Here, we identify mesenchymal stem/stromal cell (MSC)-derived lactate as a signaling metabolite that reprograms monocyte metabolism and differentiation. GM-CSF enhanced glycolytic activity in bone marrow cells and expanded pro-inflammatory monocytes, whereas pharmacologic inhibition of glycolysis with 2-deoxy-D-glucose reversed these effects. MSC coculture suppressed glycolytic activation and redirected monocyte differentiation toward an immunosuppressive phenotype. MSCs produced lactate in a hypoxia-inducible factor 1α (HIF-1α)-dependent manner, and blocking lactate production through oxamate treatment or HIF1A knockdown attenuated the effects of MSCs on differentiating monocytes, whereas exogenous lactate recapitulated them. In experimental autoimmune uveoretinitis, intravenous administration of MSCs ameliorated the disease, but oxamate-pretreated or HIF1A-knockdown MSCs exhibited reduced efficacy. The HIF-1α-lactate axis may therefore represent a targetable pathway for optimizing MSC-based therapies and for developing lactate-centered interventions in autoimmune diseases.
    Keywords:  CP: immunology; CP: metabolism; HIF-1α; MSC; bone marrow; experimental autoimmune uveoretinitis; glycolysis; lactate; mesenchymal stem/stromal cell; monocyte; myeloid-derived suppressor cell
    DOI:  https://doi.org/10.1016/j.celrep.2026.118104
  7. Alzheimers Dement. 2026 Oct;22(10): e71909
    Spatiotemporal heterogeneity and dynamic evolution of microglial glucose metabolic reprogramming in Alzheimer's disease.
    Yuan Chen, Fuyao Li, Junlei Zhang, Mingqing Wei, Jingnian Ni, Ting Li, Lulu Yao, Jinzhou Tian, Jing Shi.
      Alzheimer's disease (AD) is accompanied by persistent disturbances in brain energy metabolism, and microglial glucose metabolic reprogramming constitutes an important link among pathological protein deposition, neuroinflammation, and impaired clearance. This review examines these metabolic changes across disease stages, brain regions, and plaque-associated microenvironments and proposes a dynamic state-composition model. In this model, microglia in different metabolic states coexist, and their relative proportions and spatial distribution change as AD progresses. In early disease or during active phagocytosis, some microglia show enhanced glycolytic and oxidative phosphorylation (OXPHOS) programs. Under persistent pathological stress, increased glucose uptake may not translate into effective energy production and can coexist with inflammation and impaired lipid metabolism. In late disease, microglia with reduced metabolic capacity and impaired phagocytosis become more prevalent. However, higher expression of OXPHOS-related genes in some microglial states associated with tau pathology does not necessarily indicate improved mitochondrial respiration. These population-level patterns do not imply that individual microglia follow a fixed sequence of metabolic changes. Longitudinal cell tracking and microglia-specific metabolic flux measurements are needed to test this model and inform interventions tailored to disease stage and microglial state.
    Keywords:  Alzheimer's disease; glucose metabolism; glycolysis; immunometabolism; metabolic reprogramming; microglia; oxidative phosphorylation; spatial heterogeneity
    DOI:  https://doi.org/10.1002/alz.71909
  8. Nat Rev Cancer. 2026 Oct 07.
    Boosting CAR T cell efficacy in cancer with metabolic insights from design to diet.
    Jessica Morgan, Sarah MacPherson, Julian J Lum.
      Chimeric antigen receptor (CAR) T cell therapy has advanced the treatment of haematological cancers, but faces challenges achieving durable responses, particularly in solid tumours. Metabolism is a major determinant of CAR T cell fitness, persistence and function. The choice of co-stimulatory domain induces distinct metabolic profiles within the CAR T cell, making it crucial to consider engineering approaches that favour T cell metabolic phenotypes conducive to sustained antitumour activity. Likewise, variations in manufacturing platforms and expansion conditions, including nutrient composition, lead to distinct metabolic and functional profiles, yet the metabolic parameters in manufacturing protocols for clinical studies remain largely unstandardized. Beyond intrinsic cellular engineering, host metabolism exerts a sizeable influence on therapeutic outcome. Diet-based interventions offer a clinically accessible and scalable way to modulate systemic metabolism, which may in turn enhance CAR T cell efficacy. In this Review, we examine how metabolism integrates with CAR design, cell production and host conditioning. We highlight opportunities to leverage diet as a promising, underexplored avenue towards overcoming current barriers in treating solid tumours with CAR T cell therapy. Integrating metabolic and dietary strategies may unlock the potential for durable, effective CAR T cell therapy.
    DOI:  https://doi.org/10.1038/s41568-026-00984-2
  9. J Immunol. 2026 Oct 01. pii: vkag255. [Epub ahead of print]215(10):
    4-Octyl itaconate suppresses IFN-γ-induced MHC II expression in bone marrow-derived macrophages.
    Zhiying Zhou, Yixiu Ni, Shanshan Huang, Yijia Lin, Mingkun Yang, Yingwei Wu, Guolong Cai, Zhouxin Yang.
      Macrophages function as professional antigen-presenting cells that integrate inflammatory signals with metabolic reprogramming to shape immune responses. Itaconate, an immunometabolite derived from ACOD1/IRG1 activity in activated macrophages, has been implicated in the regulation of inflammatory responses, yet its role in interferon γ (IFN-γ)-driven antigen presentation programs remains incompletely understood. Here, we demonstrate that the itaconate derivative 4-octyl itaconate (4-OI) suppresses IFN-γ-induced antigen presentation programs in bone marrow-derived macrophages. 4-OI reduced surface major histocompatibility complex class II (MHC II) expression and downregulated key components of the antigen presentation machinery, including CIITA, H2-Ab1, and H2-Eb1. Transcriptomic analysis revealed broad suppression of IFN-γ-responsive immune pathways, particularly those associated with antigen processing and inflammatory signaling. Mechanistically, 4-OI attenuated IFN-γ-induced phosphorylation of JAK1, JAK2, and STAT1, and pharmacological inhibition of JAK signaling phenocopied its effects on MHC II expression, implicating involvement of the IFN-γ-JAK-STAT1-CIITA axis. In vivo, 4-OI similarly reduced IFN-γ-induced MHC II expression in splenic macrophages, accompanied by decreased PD-L1 expression as a parallel marker of macrophage activation. Together, these findings identify 4-OI as an immunometabolic regulator of IFN-γ-driven macrophage activation, associated with modulation of the JAK-STAT1-CIITA signaling axis and suppression of antigen presentation programs.
    Keywords:  4-octyl itaconate; IFN-γ; MHC II; inflammation; macrophages
    DOI:  https://doi.org/10.1093/jimmun/vkag255
  10. Front Cell Infect Microbiol. 2026 ;16 1877832
    Salmonella typhimurium exploits macrophage-derived arginine as an intracellular signal for SPI-2 virulence gene activation.
    Xinyue Wang, Shuai Ma, Ting Ye, Houliang Guo, Yiming Wang, Xiaolin Yan, Yuyang Sun, Mengjie Zhao, Lingyan Jiang, Lu Feng.
       Background: Arginine contributes to host defense by serving as a substrate for inducible nitric oxide synthase (iNOS) to produce antimicrobial nitric oxide (NO). However, how bacterial pathogens respond to host arginine metabolism remains poorly understood.
    Results: We found that Salmonella Typhimurium (S. Tm) infection causes arginine accumulation in macrophages. This accumulation is associated with two concurrent mechanisms: enhanced arginine import via upregulation of the CAT2 transporter, and pathogen-mediated suppression of host iNOS expression. S. Tm then exploits this accumulated arginine as an intracellular signal to upregulate virulence gene expression and promote its replication. Mechanistically, arginine activates the type III secretion system (T3SS) encoded by Salmonella pathogenicity island 2 (SPI-2) via the bacterial transcriptional regulator ArgR, which binds to the promoter of ssrA, the key regulator of SPI-2, in an arginine-dependent manner. Disruption of argR impairs S. Tm intracellular replication and attenuates virulence in mice.
    Conclusions: These findings reveal that S. Tm co-opts the host's arginine-mediated immune response by sensing macrophage-derived arginine as a signal to initiate its virulence program, revealing a pathogen adaptation strategy that links metabolic sensing to virulence activation.
    Keywords:  ArgR; SPI-2 T3SS; Salmonella typhimurium; arginine; virulence regulation
    DOI:  https://doi.org/10.3389/fcimb.2026.1877832
  11. Cell Biol Int. 2026 Oct;50(10): e70217
    Immunometabolic Reprogramming in the Bone Marrow Niche: Mechanisms, Plasticity, and Precision Therapeutic Targeting.
    Adrian Khu, Alexander P Marpaung, Princella Halim, Amama Rani, Putri Cahaya Situmorang, Alexander Patera Nugraha, Fahrul Nurkolis, Rosy Iara Maciel de Azambuja Ribeiro, Bonglee Kim, Rony Abdi Syahputra.
      The bone marrow (BM) microenvironment is increasingly recognized as a dynamic immunometabolic niche that critically governs hematologic malignancies and BM-associated disorders, including acute myeloid leukemia (AML), multiple myeloma, myelodysplastic syndromes (MDS), metastatic infiltration, and aplastic anemia. At the core of this ecosystem, hematopoietic and leukemic stem cells (HSCs/LSCs) undergo profound immunometabolic reprogramming driven by complex interactions with stromal and immune components. Mesenchymal stromal cells (MSCs) enhance mitochondrial fitness and oxidative phosphorylation (OXPHOS) in malignant cells via cysteine supply and mitochondrial transfer, while endothelial cells regulate niche retention and survival through CXCL12 and adhesion molecules such as E-selectin. Adipocytes further support tumor bioenergetics by supplying free fatty acids (FFAs) that fuel fatty acid oxidation (FAO), whereas M2-polarized macrophages reinforce immunosuppressive and metabolic adaptations through arginase-1 activity and FAO-dependent pathways. These coordinated interactions promote a metabolically flexible phenotype characterized by shifts between OXPHOS and glycolysis, activation of FAO and glutamine metabolism, and engagement of one-carbon metabolism, collectively sustaining malignant progression. Concurrently, the BM niche establishes a profoundly immunosuppressive milieu mediated by myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), indoleamine 2,3-dioxygenase 1 (IDO1)-driven kynurenine signaling, lactate-induced acidosis, and HIF-1α-mediated pseudo-hypoxia, which together impair anti-tumor immunity and facilitate disease persistence. Importantly, these immunometabolic dependencies provide actionable therapeutic vulnerabilities. Targeted strategies, including IDH1/2 inhibitors (ivosidenib and enasidenib), BCL-2 inhibition (venetoclax), niche-disrupting agents (plerixafor and uproleselan), OXPHOS inhibitors (IACS-010759 and metformin), and immunometabolic interventions such as IDO1 inhibitors and CAR-T therapies represent emerging precision approaches. Collectively, this integrative framework highlights the BM microenvironment as a central regulator of cancer cell metabolism and immune evasion, underscoring the potential of immunometabolic targeting to overcome therapeutic resistance and enable next-generation precision medicine in hematologic diseases.
    Keywords:  bone marrow microenvironment; epigenetic regulation; hematological malignancies; immunometabolism; metabolic reprogramming
    DOI:  https://doi.org/10.1002/cbin.70217
  12. Eur J Immunol. 2026 Oct;56(10): e70293
    Integrated Metabolomic and Bioenergetic Profiling Reveals Axl as a Key Regulator of Macrophage Homeostasis.
    Jesuino R M Ferreira, Thais S Rigoni, Monique S Leandro, Kamila Guimarães-Pinto, Letícia R Ramos, André L A Costa, Clara F Carvalho, Caroline F Martiniuc, Isadora A Oliveira, Carolina Maia, Júlia Moratelli, Jefferson A Leite, Verônica S Pinto, Adriane Todeschini, Antônio Galina, Alessandra A Filardy.
      The TAM receptor Axl is essential for efferocytosis and inflammatory regulation, but its role in macrophage immunometabolic homeostasis remains unclear. Here, we combined phenotypic, functional, metabolomic, and bioenergetic analyses to define how Axl deficiency alters peritoneal macrophages (PMs) under steady-state conditions. Axl- / - PMs exhibited reduced cell numbers, downregulation of resident macrophage markers, and increased Ly6C expression, indicating a shift toward a less mature, monocyte-like phenotype. Functionally, these cells showed impaired inflammatory activation, with reduced nitrite release, diminished LPS-induced ROS production, and lower mitochondrial ROS. Metabolomic profiling revealed broad disruption of central carbon metabolism, including reduced glycolytic intermediates, depletion of tricarboxylic acid (TCA) cycle metabolites, and decreased NAD+/NADH and NADP+/NADPH pools. Despite reduced glycolytic flux, preserved pyruvate levels suggested compensatory carbon utilization. Bioenergetic assessment demonstrated pronounced mitochondrial dysfunction, characterized by reduced maximal respiration, elevated proton leak, and limited oxidative phosphorylation flexibility. Redox balance was also impaired, with decreased GSH, GSSG, and dehydroascorbic acid and increased ophthalmic acid, consistent with elevated oxidative stress. Systemically, Axl- / - mice displayed hepatic redox imbalance and biochemical signs of liver dysfunction. Collectively, these findings identify Axl as a central regulator of macrophage identity, mitochondrial performance, and redox resilience, required for maintaining local and systemic homeostasis.
    Keywords:  Axl receptor; immunometabolism; oxidative stress; peritoneal macrophages
    DOI:  https://doi.org/10.1002/eji.70293
  13. Brain Behav Immun. 2026 Oct 03. pii: S0889-1591(26)00779-8. [Epub ahead of print] 107031
    Immunometabolic alterations in post-traumatic stress disorder.
    Jelena Brasanac, Linda El-Ahmad, Emma Mollerup, Stefanie Gamradt, Luisa Gruenberg, Daria Shyshko, Victoria Stiglbauer, Kim Zimbalski, Nikola Schoofs, Kathlen Priebe, Felix Wülfing, Simon Guendelman, Tolou Maslahati, Stefanie Koglin, Christian Otte, Isabel Dziobek, Stefan Roepke, Stefan M Gold.
      Post-traumatic stress disorder (PTSD) has been linked to various alterations within the immune system, yet the metabolic programming of immune cells remains unexplored. In the current exploratory cross-sectional study, we interrogated immunometabolic function by applying cell-specific metabolic flow cytometry, serum biomarker profiling, and targeted gene expression analysis in peripheral blood mononuclear cells from patients with PTSD (n = 34) compared with healthy controls (n = 32). PTSD was associated with elevated serum IL-6 (p = 0.005) and higher glycolysis- and oxidative pentose phosphate pathway-related markers (identified by CITRUS/SAM using a prespecified FDR threshold of 1%): lactate dehydrogenase (LDH) and glucose-6-phosphate dehydrogenase (G6PD) across adaptive and innate immune cell subsets (CD4⁺ T, CD8⁺ T, B cells, NK cells, monocytes; Cohen's d = 0.51-0.74). CD4⁺ T cells additionally showed elevated glucose transporter 1 (GLUT1, Cohen's d = 0.76), CD8⁺ T cells demonstrated enhanced carnitine palmitoyl transferase 1A (CPT1a, Cohen's d = 0.54) expression, and monocytes exhibited increased acetyl-CoA carboxylase (ACAC, Cohen's d = 0.69). Expression of inflammatory- and stress-related genes was largely comparable between groups. Together, these data provide preliminary evidence for immunometabolic alterations in PTSD at both cellular and systemic levels. These results could contribute to understanding potential pathophysiological mechanisms and support further investigation of immunometabolism in PTSD.
    Keywords:  Immunometabolism; Inflammatory cytokines; Metabolic flow cytometry; Post-traumatic stress disorder
    DOI:  https://doi.org/10.1016/j.bbi.2026.107031
  14. Cell Metab. 2026 Oct 06. pii: S1550-4131(26)00379-7. [Epub ahead of print]38(10): 1943-1945
    Glutamine metabolism keeps pathogenic hepatic CD4+ T cells in check.
    Haiguang Wang, Andrew Hakeem, Xavier S Revelo.
      Sawada et al. show that glutamine metabolism through glutaminolysis restrains O-GlcNAcylation and pathogenic inflammatory cytokine production by hepatic CD4+ T cells during MASLD. Glutamine supplementation restores hepatic glutamine availability and limits liver injury, and these findings reveal a tissue-specific metabolic checkpoint that restrains inflammatory T cell function during steatohepatitis.
    DOI:  https://doi.org/10.1016/j.cmet.2026.09.004
  15. Trends Immunol. 2026 Oct 08. pii: S1471-4906(26)00260-7. [Epub ahead of print]
    Context-dependent roles of ketone metabolism in intestinal inflammation.
    Wenxuan Dong, Chi Yan, Bethany Korwin-Mihavics, Margaret Alexander.
      Ketone metabolism is traditionally viewed as an alternative metabolic pathway providing energy during carbohydrate deprivation through the production and utilization of ketone bodies. Ketone bodies also function as signaling molecules regulating immune and metabolic processes. Accumulating evidence shows that ketone metabolism influences diverse diseases and immune responses, including inflammation, autoimmunity, and infection. Recently, ketone metabolism has been associated with inflammatory bowel disease (IBD), a chronic inflammatory disorder of the intestine, although reported effects are heterogeneous and context-dependent. In this review, we synthesize current evidence on ketone metabolism in IBD and intestinal inflammation, highlighting its roles in barrier integrity, immune regulation, and microbiota interactions. We also discuss potential mechanisms underlying divergent outcomes and outline key questions for future research.
    Keywords:  gut microbiome; immunometabolism; inflammatory bowel disease; ketone bodies; β-hydroxybutyrate
    DOI:  https://doi.org/10.1016/j.it.2026.09.005
  16. Nat Metab. 2026 Oct 06.
    L-Arginine inhibits NLRP3 inflammasome activation.
    Feng Liu, Wanxin Zhuang, Yuan Yang, Wenting Zhao, Chao Zhang, Siyuan Li, Xudong Liu, Qingyuan Cao, Shunguo Zhu, Bingyu Liu, Xiangyu Ma, Lintai Da, Chengjiang Gao.
      Nutritional status and metabolic homeostasis are intricately associated with the inflammatory response. However, the direct mechanistic link between nutrition, metabolism and inflammation remains unclear. Here, we show that the amino acid L-arginine (L-Arg) is a potent endogenous inhibitor of the NLRP3 inflammasome, a central component of the inflammatory signalling pathway. We show that L-Arg binds directly to the Asp31 site of the NLRP3 protein, blocking its interaction with the adaptor ASC and subsequent inflammasome assembly and activation. L-Arg supplementation inhibits the NLRP3 inflammasome activation in macrophages, while deprivation promotes it. Treatment with L-Arg in mice alleviates monosodium urate crystal-induced arthritis and aluminium-induced peritonitis. In addition, L-Arg supplementation alleviates neuroinflammation and motor deficits in mouse models of Parkinson's disease, whereas L-Arg deprivation exacerbates pathology. In patients with Parkinson's disease, L-Arg levels are reduced in serum. Our study establishes L-Arg supplementation as a promising therapeutic avenue for managing NLRP3-driven inflammatory pathologies.
    DOI:  https://doi.org/10.1038/s42255-026-01636-3
  17. Front Immunol. 2026 ;17 1953443
    Microbiota-derived metabolic priming of CAR-T cell fitness: a translational framework for next-generation cell therapy.
    Simone Melchiorri, Ignazio Castagliuolo.
      Chimeric antigen receptor T-cell (CAR-T) therapy has transformed the treatment of hematologic malignancies, yet durable responses remain inconsistent and clinically significant toxicities persist. Emerging evidence identifies the gut microbiota as an extratumoral determinant of CAR-T efficacy, persistence, and toxicity. However, taxonomic signatures associated with clinical outcomes show limited reproducibility and are influenced by antibiotics, geography, diet, and methodological heterogeneity. Building on prior reviews addressing microbiome-CAR-T associations and CAR-T-cell immunometabolism separately, here we synthesize clinical, translational, and preclinical evidence into an integrated, metabolome-centered framework spanning the full CAR-T treatment and manufacturing trajectory. Broad-spectrum antibiotic exposure disrupts microbial metabolic output, depleting short-chain fatty acids, indole derivatives, and other bioactive metabolites, and has been associated with inferior clinical outcomes in several cohorts, although these associations are heterogeneous and may be confounded by baseline disease severity, systemic inflammation, and infection-related factors. Experimental studies further indicate that butyrate, valerate, inosine, indoles, and succinate modulate mitochondrial fitness, memory differentiation, epigenetic programming, cytotoxicity, and exhaustion through interconnected metabolic and receptor-mediated pathways. We propose that the gut microbiota acts as a distributed metabolic organ whose collective output shapes CAR-T-cell fitness and therapeutic response. This framework supports the development of metabolite-based biomarkers and therapeutic strategies, including microbiota-conscious antibiotic stewardship, ecosystem restoration, dietary or metabolite-based interventions, and ex vivo metabolic conditioning during CAR-T manufacturing. Shifting from descriptive microbiome profiling to functional metabolomics may improve both prediction and optimization of CAR-T therapy.
    Keywords:  CAR-T cell therapy; gut microbiota; immunometabolism; microbial metabolomics; microbiota-derived metabolites; short-chain fatty acids
    DOI:  https://doi.org/10.3389/fimmu.2026.1953443
  18. Cancer Res. 2026 Oct 08.
    Sodium-Glucose Cotransporter SGLT2 Supports Metabolic Fitness and Ferroptosis Resistance in CAR-T Cells to Enhance Activity Against Solid Tumors.
    Yaoxin Gao, Xinbin Yang, Xiaowen Mao, Luoming Zhang, Pengju Lv, Baodong Ma, Fuli Qin, Ranran Jin, Lin Wang, Songge Liu, Jianping Ye, Shoukui Hu, Dandan Guo, Xu Wu, Xiwen Ma, Juntang Lin, Zhengyuan Xia.
      Antitumor T-cell function is tightly coupled with cellular metabolism, which is severely compromised by glucose deprivation and elevated sodium chloride (NaCl) in the solid tumor microenvironment (TME). Here, we demonstrated that glucose restriction markedly impaired activation, cytotoxicity, and persistence of CAR-T cells while promoting exhaustion, whereas high NaCl partially reversed these defects. Overexpression of the sodium-glucose cotransporter SGLT2 in CAR-T cells to simultaneously enhance glucose and NaCl uptake led to stronger antitumor activity in multiple solid tumor xenograft models. Mechanistically, SGLT2 overexpression elevated glycolysis and mitochondrial fitness, inhibited ferroptosis, and activated the AKT-mTOR pathway. These findings establish a metabolic engineering strategy that boosts glucose utilization in CAR-T cells to overcome TME stress and enhance solid tumor control.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-1157
  19. Front Immunol. 2026 ;17 1917176
    Histone lactylation: a metabolic-epigenetic bridge linking glycolysis to salivary gland fibrosis in Sjögren's disease.
    Yang Qin, Huayan Tang.
      Sjögren's disease (SjD) is a chronic, systemic autoimmune disorder characterized by lymphocytic infiltration and progressive loss of exocrine gland function. Despite advances in understanding its immunopathogenesis, the molecular mechanisms governing the transition from inflammation to irreversible salivary gland fibrosis remain obscure. Emerging evidence suggests that the crosstalk between metabolic reprogramming and epigenetic modifications profoundly shapes the local inflammatory microenvironment and accelerates disease progression. Histone lactylation, a recently discovered lactate-derived epigenetic mark, directly couples enhanced glycolytic activity and lactate accumulation with transcriptional regulation, thereby serving as a pivotal metabolic-epigenetic bridge. This review systematically examines the potential role of histone lactylation in SjD salivary gland pathology. We delineate the enzymatic machinery of lactylation, the metabolic origins of lactate within the inflamed microenvironment, and the functional implications for immune cell polarization, epithelial-mesenchymal transition, and myofibroblast activation. While direct evidence in SjD is currently lacking, we synthesize findings by integrating immunometabolism, epigenetic rewiring, and tissue fibrogenesis, we aim to establish histone lactylation as a transformative framework for understanding SjD pathogenesis and highlight its translational potential for novel biomarkers and therapeutic interventions.
    Keywords:  Sjögren’s disease; epigenetic regulation; histone lactylation; lactate microenvironment; metabolic reprogramming; salivary gland fibrosis
    DOI:  https://doi.org/10.3389/fimmu.2026.1917176
  20. Cancer Lett. 2026 Oct 07. pii: S0304-3835(26)00639-7. [Epub ahead of print]661 218875
    Coordinated nicotinamide metabolism by NAMPT and NNMT: Integrating metabolic, epigenetic and immune crosstalk.
    Irene Fiorilla, Beatrice Ghezzi, Agata Carreira, Andrea Mantovan, Alessia Ponzano, Filippo Casone, Giulia Rizza, Valentina Audrito.
      Cancer cells adapt to microenvironmental cues through the coordinated integration of metabolic reprogramming, epigenetic remodeling, and immune regulation. An emerging central regulator of this adaptive network is coordinated nicotinamide metabolism, which controls both nicotinamide adenine dinucleotide (NAD) biosynthesis and cellular methylation potential. Within this network, the nicotinamide-metabolizing enzymes nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide N-methyltransferase (NNMT) govern the metabolic fate of nicotinamide (NAM), thereby coupling energy metabolism to epigenetic regulation and adaptive cellular responses. NAMPT, the rate-limiting enzyme of the NAD salvage pathway, sustains intracellular NAD pools required for redox homeostasis, mitochondrial function, DNA repair, and stress responses. Conversely, NNMT diverts NAM from NAD biosynthesis by catalyzing its methylation while consuming S-adenosylmethionine (SAM), thereby creating a methylation sink that remodels chromatin organization and promotes transcriptional plasticity. Beyond intracellular metabolism, coordinated nicotinamide metabolism extends to the tumor microenvironment through extracellular mediators, including extracellular NAMPT (eNAMPT), the emerging extracellular functions of NNMT (eNNMT) and its metabolite 1-methylnicotinamide (1-MNA), which regulate stromal remodeling, immune cell function, chronic inflammation, and immune evasion. Collectively, these complementary intracellular and extracellular activities establish a multilevel adaptive network that integrates metabolic homeostasis, epigenetic remodeling, and immunometabolic communication, thereby promoting tumor plasticity, therapeutic adaptation, and resistance. Here, we propose a conceptual framework in which NAMPT and NNMT function as complementary regulators of coordinated nicotinamide metabolism operating across interconnected intracellular and extracellular levels. By integrating metabolic, epigenetic, and immune crosstalk into a unified model of tumor adaptation, this perspective provides new insights into tumor progression and therapy resistance while highlighting context-dependent opportunities for mechanism-based combination therapies in cancer.
    Keywords:  Drug resistance; Epigenetics; Immune crosstalk; Metabolism; Microenvironment; NAD; NAMPT; NNMT
    DOI:  https://doi.org/10.1016/j.canlet.2026.218875
  21. Int Immunopharmacol. 2026 Oct 09. pii: S1567-5769(26)01361-5. [Epub ahead of print]190 117513
    Monosodium urate induces macrophage M1 polarization and endothelial apoptosis via the HIF1A-glycolysis axis.
    Fei Pan, Mengting Hu, Yuxuan Zou, Yantong Wan, Jia Zhao, Mei Liu.
       BACKGROUND: Monosodium urate (MSU) crystal deposition causes gout, which causes inflammation mediated by macrophages. HIF1A regulates inflammation and cellular metabolism, but its role in MSU-induced macrophage polarization and consequent endothelial dysfunction remains undefined.
    METHODS: This study analyzed the public transcriptome (GSE242872) to identify key genes in MSU-stimulated mouse ankle tissue. THP-1 - derived macrophages (THP-1 - DM) and stimulated with MSU. Loss- and gain-of-function studies of HIF1A were performed using siRNA or overexpression, with or without 2-DG, a glycolysis inhibitor. Polarization markers and glycolytic effectors were assessed by qRT-PCR and Western blot. Conditioned medium (CM) from macrophages was applied to HUVECs to evaluate endothelial viability, apoptosis, and inflammation.
    RESULTS: Bioinformatic screening highlighted HIF1A as a hub gene upregulated at 8 h and 24 h after MSU exposure. Experimentally, MSU drove THP-1-DM toward a pro-inflammatory M1 phenotype and suppressed M2 markers. MSU also induced HIF1A and upregulated glycolytic enzymes (PDK1, PGK1, GLUT1, GCK, PKM2). HIF1A knockdown attenuated MSU-induced M1 markers, restored M2 markers, and blunted glycolytic activation; conversely, HIF1A overexpression enhanced glycolytic enzymes and M1 polarization while inhibiting M2, effects reversed by 2-DG. CM from MSU-stimulated or HIF1A-overexpressing macrophages reduced HUVECs viability, increased apoptosis, and elevated endothelial inflammation genes, whereas CM from HIF1A-silenced cells mitigated these changes; 2-DG partially rescued HIF1A-overexpression effects.
    CONCLUSION: MSU drives macrophages toward an M1 phenotype through HIF1A-dependent glycolytic reprogramming, and the resulting macrophage secretome promotes endothelial inflammation. Targeting HIF1A-mediated metabolic pathways may provide therapeutic strategies for gout-associated vascular complications.
    Keywords:  Endothelial apoptosis; Glycolysis; Gout; HIF1A; Macrophage polarization; Monosodium urate
    DOI:  https://doi.org/10.1016/j.intimp.2026.117513
  22. Biochem Pharmacol. 2026 Oct 03. pii: S0006-2952(26)00864-6. [Epub ahead of print]254(Pt 3): 118522
    Cebpb/JAK2/STAT3 signaling pathway mediated M1 macrophage polarization and metabolic rewiring drive COPD pathogenesis.
    Qingshuang Mu, Qin Luo, Ye Yang, Reyila Yahefu, Mairemugu Abudureyimu, Qin Wang, RuiSheng-Li.
      Chronic obstructive pulmonary disease (COPD) is asyndrome characterized by airflow limitation, and its pathogenesis is not fully understood. This study intends to conduct a systematic analysis of the key cellular and metabolic remodeling mechanisms involved in the occurrence and development of COPD. A murine COPD model was established and analyzed by histopathology, molecular assays, scRNA-seq, and targeted metabolomics to investigate pulmonary inflammation, microenvironment changes, cellular composition, and signaling dysregulation. Furthermore, CCAAT enhancer-binding protein β (Cebpb) was knocked down in M1-polarized macrophages to assess its role in gene expression and energy metabolism reprogramming. The results showed that pulmonary inflammation was increased in COPD mice, with elevated inflammatory cell infiltration, pro-inflammatory cytokine upregulation, and enhanced M1 macrophage polarization. Specifically, scRNA-seq revealed immune cell landscape remodeling, with T cells as central intercellular mediators. Additionally, macrophage differentially expressed genes were enriched in energy metabolism pathways, including ribosome and oxidative phosphorylation. Moreover, targeted metabolomics demonstrated substantial metabolic alterations in lung tissues and macrophages, particularly in ABC transporters, amino acid metabolism, and the tricarboxylic acid (TCA) cycle. Mechanistically, the Cebpb/janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) axis was strongly activated in COPD lungs and M1-polarized macrophages. Functionally, Cebpb silencing suppressed this pathway activity, macrophage invasion, and M1 polarization, whereas exogenous JAK2/STAT3 activation reversed these effects. Consistently, RNA-seq confirmed that Cebpb regulates macrophage gene expression and metabolic profiles. In conclusion, the Cebpb/JAK2/STAT3 pathway is activated in COPD and promotes progression by driving M1 macrophage polarization and orchestrating downstream metabolic reprogramming.
    Keywords:  Cebpb/JAK2/STAT3 signaling pathway; Chronic obstructive pulmonary disease; Inflammation; Macrophages; Metabolomics; Transcriptome sequencing
    DOI:  https://doi.org/10.1016/j.bcp.2026.118522
  23. Cell Chem Biol. 2026 Oct 06. pii: S2451-9456(26)00333-8. [Epub ahead of print]
    Non-enzymatic protein modifications at the interface of metabolism and immunity.
    Nicole S Walker, James J Galligan, Yael David, Anna Knörlein.
      Immune cells are highly metabolically active throughout their life cycle, leading to elevated levels of a variety of reactive metabolites including reactive oxygen species, sugars, and lipid peroxidation products. These molecules covalently modify proteins, resulting in post-translational non-enzymatic covalent modifications (NECMs). Similar to their enzymatic counterparts, NECMs impact proteins' structure, stability, localization, function, and interactome, thereby shaping cellular behavior, providing an additional layer of regulation to leukocyte function. With increasing evidence linking metabolic dysregulation to dysfunction of immune cells, it is becoming critical to understand the role NECMs play in regulating immune cell fate. This review highlights recent advances in our understanding of NECMs in immune cell function, including their roles in inflammation and immune responses. We further discuss emerging chemical biology technologies to detect, interrogate, and manipulate these modifications while outlining key challenges that will shape future studies of non-enzymatic protein modifications in immune regulation.
    Keywords:  T cells; epigenetics; glycolysis; immunology; macrophages; metabolism; non-enzymatic modifications; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.chembiol.2026.09.005
  24. Metabolism. 2026 Oct 05. pii: S0026-0495(26)00308-2. [Epub ahead of print] 156795
    MINDY1 drives metabolic-immune crosstalk via OGT-UGP2-UDPG axis to promote immunosuppressive macrophage reprogramming.
    Kejing Zhang, Kui Chen, Xinyu Mi, Yilin Pan, Desheng Xiao, Shuang Liu, Ledu Zhou, Yongguang Tao, Jing Cao, Jianing Tang.
      The efficacy of immune checkpoint blockade is limited in hepatocellular carcinoma (HCC) due to tumor-intrinsic mechanisms. Here we identify the deubiquitinase MINDY1 as a central regulator of metabolic-immune crosstalk that drives immunotherapy resistance in HCC. MINDY1 is significantly upregulated in immunotherapy non-responders and correlates with poor prognosis and increased M2-like macrophage infiltration. Mechanistically, MINDY1 stabilizes O-GlcNAc transferase (OGT) by removing K48-linked ubiquitin chains, thereby enhancing O-GlcNAcylation of uridine diphosphate glucose pyrophosphorylase 2 (UGP2) at T152. This modification promotes UGP2 enzymatic activity and increases uridine diphosphate glucose (UDPG) synthesis and extracellular accumulation. Tumor-derived UDPG acts as an extracellular immunometabolite that directly binds to PPARγ in macrophages, promoting its nuclear translocation and transcriptional activation. UDPG-driven PPARγ signaling enhances fatty acid oxidation and induces M2-like polarization, suppressing CD8+ T-cell cytotoxicity and establishing an immunosuppressive tumor microenvironment. Targeting MINDY1 remodels macrophage metabolism, restores CD8+ T-cell effector function, and significantly enhances anti-PD-1 efficacy in vivo. Our findings uncover a previously unrecognized mechanism that links tumor proteostasis to immune suppression and identify MINDY1 as a promising therapeutic target for overcoming immunotherapy resistance in HCC.
    Keywords:  Deubiquitination; MINDY1; O-GlcNAcylation; Tumor-associated macrophages; UDP-glucose
    DOI:  https://doi.org/10.1016/j.metabol.2026.156795
  25. Cell. 2026 Oct 06. pii: S0092-8674(26)01122-0. [Epub ahead of print]
    Cancer competition for vitamin B2 creates metabolic checkpoint for T cell ferroptosis.
    Huanpeng Chen, Chao Li, Yujing Ke, Zilong Wu, Ziwei Ou, Nanqi Huang, Zhenyu Lin, Huixin Gao, Xuehu Xu, Lijuan Lu, Zhaofeng Huang, Yingjie Bian.
      Metabolic competition between tumors and T cells drives immune evasion, but the transporters and mechanisms remain largely elusive. Here, we establish the CareSLCs platform and identify that SLC52A3-mediated vitamin B2 (VB2) uptake is indispensable for T cell antitumor immunity. Mechanistically, VB2 deficiency impairs mitochondrial respiration and glutathione regeneration, leading to mitophagy, labile iron accumulation, and lipid peroxidation that trigger T cell ferroptosis. Unexpectedly, tumors preferentially employ SLC52A2, not SLC52A3, to scavenge VB2 and outcompete T cells. Tumor SLC52A2 ablation enhances T cell function in immunocompetent hosts without appreciably affecting intrinsic tumor growth. Clinically, high tumoral SLC52A2 correlates with T cell dysfunction and poor survival, whereas dietary VB2 intake is associated with reduced cancer risks. Thus, VB2 supplementation or SLC52A3 overexpression augments CAR-T cell antitumor efficacy. Our results suggest that tumoral VB2 competition establishes a metabolic checkpoint driving T cell ferroptosis and that enhancing VB2 uptake reinvigorates T cells to improve cancer immunotherapy.
    Keywords:  CAR-T cell therapy; SLC52A2; SLC52A3; ferroptosis; metabolic competition; vitamin B2
    DOI:  https://doi.org/10.1016/j.cell.2026.09.020
  26. Cell Rep. 2026 Oct 06. pii: S2211-1247(26)01168-X. [Epub ahead of print]45(10): 118089
    Deoxysphingolipids activate cGAS-STING and enhance antitumor immunity.
    Suchandrima Saha, Fabiola N Velazquez, Fatemeh Dehpanah, Brianna L Bergfalk, Samantha Mulkeen, Karissa J Lopez, Cungui Mao, David C Montrose.
      Deoxysphingolipids (deoxySLs) are a class of non-canonical sphingolipids that can adversely impact mitochondrial function. Mitochondrial DNA release resulting from mitochondrial disruption can activate the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, and in turn, promote antitumor immunity. Here, we investigated whether inducing deoxySL accumulation in colon cancer cells drives immune-specific, antitumor effects. We show that depleting serine increased deoxySLs and enhanced immune cell infiltration in colon tumors, in parallel with suppressing tumor growth. Elevating tumor deoxySL levels in mice through mutation of serine palmitoyltransferase and feeding a high alanine diet exerted similar effects, including immune-mediated tumor growth suppression. Work conducted in multiple in vitro systems identified deoxySLs as key triggers of cGAS-STING activation, an effect mediated by the release of mitochondrial DNA under mitochondrial stress. Collectively, these findings demonstrate that deoxySLs drive antitumor immunity and identify a previously unrecognized metabolic strategy for cancer therapy.
    Keywords:  CP: cancer; CP: metabolism; amino acids; chemokines; colorectal cancer; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2026.118089
  27. Microbiology (Reading). 2026 Oct;172(10):
    Fatty acid-dependent cidality in Mycobacterium avium and Mycobacterium abscessus: intracellular acidification by itaconic acid.
    Hannah Lynch, Ronan Murray, Donal J Cox, Adam J Byrne, Cormac McCarthy, Suzanne Cloonan, Claire Healy.
      Non-tuberculous mycobacterial (NTM) lung disease is now recognized as a chronic condition with considerable morbidity and mortality with incidence rising globally. This is concerning as these infections are often mis- or undiagnosed and currently available treatment regimens have lengthy (>1 year) treatment courses with variable to poor success rates. Identification of vulnerable targets and pathways in NTM pathogens is urgently needed to develop improved therapeutics. Itaconic acid (ITA), a macrophage-produced metabolite with immunomodulatory and antibacterial activity, inhibits growth of mycobacteria and here, we provide further important insights into the activity and mechanism of action for ITA. ITA displayed robust bactericidal activity against the prominent NTM pathogens Mycobacterium avium (M. avium) and M. abscessus in a pH- and fatty acid-dependent manner, conditions that these bacteria experience within phagosomes during infection. Using a genetically encoded intrabacterial pH reporter, we demonstrate that ITA induces intracellular acidification in a pH-dependent manner. This work reveals that disruption of NTM pH homeostasis is a vulnerability in these difficult-to-treat pathogens which could be exploited for therapeutic benefit.
    Keywords:  acid stress; fatty acids; itaconate; itaconic acid; non-tuberculous mycobacteria
    DOI:  https://doi.org/10.1099/mic.0.001782
  28. Front Immunol. 2026 ;17 1944289
    The immunometabolic tipping point: forecasting the systemic shift from psoriasis to psoriatic arthritis.
    Xi Chen, Can Chen, Jianqiang Yang.
      Psoriasis (PsO) is a chronic immune-mediated inflammatory disease that progresses to psoriatic arthritis (PsA) in up to 30% of patients. The transition from localized cutaneous inflammation to systemic articular involvement represents a critical window for early intervention; however, accurately predicting which patients will develop PsA remains a significant clinical challenge. Growing evidence highlights immunometabolic dysregulation as a central driver of this systemic shift. The progression from PsO to PsA is fueled by a complex interplay between immune dysregulation-centered on the IL-23/Th17 axis, tissue-resident memory T cell recirculation, and regulatory T cell dysfunction-and systemic metabolic disturbances, including obesity, insulin resistance, dyslipidemia, and adipokine imbalance. This review comprehensively examines the immunometabolic mechanisms bridging skin and joint pathology and evaluates emerging candidate biomarkers for predicting disease progression. Promising indicators include immunological markers, such as declining serum CXCL10 levels and circulating skin-homing CD8+CCR10+ T cells, as well as metabolic signatures, including an elevated leptin-to-adiponectin ratio and distinct lipidomic and metabolomic profiles. Given the multifactorial nature of psoriatic disease, individual biomarkers often lack sufficient predictive power. Therefore, we highlight the paradigm shift toward multi-omics integration. Leveraging machine learning to synthesize genomic, transcriptomic, proteomic, metabolomic, and epigenomic data offers a powerful strategy for developing robust predictive models. The identification and validation of integrated immunometabolic biomarker profiles will facilitate early risk stratification, enable preemptive disease-modifying and lifestyle interventions, and advance precision medicine in the management of psoriatic disease.
    Keywords:  immunometabolism; multi-omics; predictive biomarkers; psoriasis; psoriatic arthritis
    DOI:  https://doi.org/10.3389/fimmu.2026.1944289
  29. J Clin Invest. 2026 Oct 06. pii: e200067. [Epub ahead of print]
    Mitochondrial metabolic dysfunction in airway epithelial cells promotes goblet cell metaplasia and more severe asthma.
    Xiuxia Zhou, Krithika S Rao, Sruti Shiva, Catharina van Heusden, Qi Wei, Nobuhiko Fukuda, Mayoko Tsuji, Angelina Kendi, Laura R Bradley, Jinming Zhao, John B Trudeau, Anuradha Ray, Richard C Boucher, Sally E Wenzel.
      Type 2 (T2) inflammation is a defining feature of asthma and associated with epithelial dysfunction, including goblet cell metaplasia and ciliary loss. Here, we investigated whether T2 inflammation and associated 15 lipoxygenase-1 (15LO1) activity alters mitochondrial metabolism in airway epithelial cells (AECs) and contributes to disease pathophysiology. Freshly isolated AECs from T2-high asthmatic participants exhibited increased oxygen consumption rates (OCR), including elevated basal respiration and proton leak, alongside reduced coupling efficiency compared to T2-low participants. These functional changes were accompanied by increased expression of electron transport chain (ETC) proteins, worse lung function and epithelial phenotypic changes. In vitro, IL-13 stimulation of differentiated AECs recapitulated these findings, inducing higher OCR, increased ETC protein levels, and enhanced proton leak while paradoxically reducing intracellular ATP. These metabolic alterations are associated with increased uncoupling protein 2 (UCP2) expression and goblet cell differentiation. Mechanistically, 15LO1 emerged as a key regulator, as ALOX15 knockdown or pharmacologic inhibition reduced OCR parameters, ETC protein expression, UCP2, and goblet cell markers, without effect on ATP levels, suggesting additional regulatory mechanisms. Collectively, these findings identify a metabolic axis linking T2 inflammation, mitochondrial dysfunction, and airway epithelial metabolism, while highlighting 15LO1-driven mitochondrial uncoupling as a potential therapeutic target in asthma. .
    Keywords:  Asthma; Inflammation; Metabolism
    DOI:  https://doi.org/10.1172/JCI200067
  30. Proc Natl Acad Sci U S A. 2026 Oct 13. 123(41): e2617216123
    Cell jamming transition is regulated by mitochondrial pyruvate transport and endocytosis.
    Alexandra Bermudez, Zoe Latham, Johnny Diaz, Weihong Yan, Jerry Chen, Dapeng Bi, Andrew S Goldstein, Jimmy K Hu, Neil Y C Lin.
      Epithelial tissues undergo dynamic transitions between fluid-like collective motion and mechanically jammed states during development, injury repair, and disease progression. However, the cellular programs that drive these transitions and regulate collective behavior remain unclear. Using a controlled crowding model integrated with live-cell imaging and time-resolved multiomics, we demonstrate that epithelial crowding triggers early metabolic changes characterized by increased mitochondrial pyruvate anaplerosis that precedes the jamming transition. Restricting mitochondrial pyruvate import increased collective cell motility and delayed jamming in crowded monolayers. This unjammed state is driven by enhanced cytoskeletal remodeling and requires RhoA-myosin II activity. Mechanistically, we show that elevated cytoskeletal signaling promotes macropinocytic uptake, which serves as a required feedback loop to maintain motility. These findings identify mitochondrial pyruvate utilization as an important regulatory input linking metabolic remodeling to the endocytic control of epithelial fluidity.
    Keywords:  collective cell migration; epithelial jamming transition; mechanobiology
    DOI:  https://doi.org/10.1073/pnas.2617216123
  31. Cell Metab. 2026 Oct 06. pii: S1550-4131(26)00384-0. [Epub ahead of print]38(10): 1935-1940
    Trajectories in immunometabolism.
    Dirk Brenner, Michela Matteoli, Carole L Linster, Felix M Wensveen, Thekla Cordes, Rafael J Argüello, Claudia Mauri, Christoph Wilhelm, Stefanie K Wculek, Luke O'Neill, Mari-Carmen Fernández-Agüera.
      Immunometabolism has rapidly evolved from an emerging area within immunology into a topic that not only impregnates most aspects of immune research but also reveals itself as a defining feature of the immune response. At the European Immunometabolism Conference celebrated in June, we asked some of the speakers to share their personal journey as researchers in this field and what questions they are currently working on.
    DOI:  https://doi.org/10.1016/j.cmet.2026.09.009
  32. bioRxiv. 2026 Aug 14. pii: 2026.08.10.743951. [Epub ahead of print]
    D-Mannose treats obesity by increasing adipose Treg cells and suppressing gut Firmicutes.
    Peter Zanvit, Junji Xu, Nancy Guo, Dunfang Zhang, Michaela Prochazkova, Thierry Gauthier, Daxesh P Patel, Alexander Cain, Wenwen Jin, Andrew Bynum, Frank J Gonzalez, Yasmine Belkaid, WanJun Chen.
      Early-life microbiota represent an indispensable factor for the proper development and function of host metabolism and the immune system. We have demonstrated that neonatal exposure to antibiotics for the first 3 weeks (NeoATB) leads to obesity in adulthood, characterized by gut microbiota dysbiosis and dysregulated immune responses. Here, we demonstrate that feeding D-mannose suppresses NeoATB-induced obesity, accompanied by improved glucose tolerance and decreased insulin resistance. Mechanistically, D-mannose feeding decreased hypoxia and increased oxygenation and recovery of metabolic activity of adipocytes. D-mannose restored CD4 + Foxp3 + ST2 + Tregs, leading to a reduction of Th1 pro-inflammatory cells in the adipose tissue of NeoATB mice. Significantly, we revealed that D-mannose treatment reversed the dysregulated ratios of phylum Firmicutes to phylum Bacteroidetes in obese NeoATB mice, which was surprisingly attributed to D-mannose-mediated suppression of the growth of Firmicutes rather than an increase in the growth of Bacteroidetes. These findings should have therapeutic implications for the treatment of obesity in human patients.
    DOI:  https://doi.org/10.64898/2026.08.10.743951
  33. Front Immunol. 2026 ;17 1861435
    VARS2 deficiency drives seronegative myasthenia gravis pathology via mitochondrial, immune, and neuromuscular dysregulation.
    Zhaojie Lyu, Bo Yang, Yaobin Zhou, Meng Shi, Zhihao Wang, Sa Song, Xinwen Zhang, Jing Tian.
      Seronegative myasthenia gravis (SNMG) is a clinically heterogeneous subtype of myasthenia gravis (MG) that lacks the classical pathogenic autoantibodies used in routine diagnosis, leaving the underlying mechanisms poorly defined. Integrative genetic and single-cell transcriptomic analyses identified VARS2 as an MG-associated candidate gene with particular relevance to SNMG. VARS2 dysregulation was predominantly observed in CD4+ T cells, especially in the SNMG subgroup. To evaluate its in vivo relevance to SNMG, we established a zebrafish vars2 knockdown model. vars2 deficiency induced a myasthenia-like phenotype characterized by impaired locomotor activity, abnormal skeletal muscle development, defective motor neuron formation, and reduced expression of neuromuscular junction-related genes. Furthermore, the loss of vars2 disrupted mitochondrial homeostasis, evidenced by mitochondrial structural damage, membrane potential loss, increased reactive oxygen species accumulation, and suppression of metabolic pathways. These changes were accompanied by immune dysregulation, marked by CD4+ T cell/Th17-associated inflammatory activation, reduced expression of Treg-related genes, and increased neutrophil and macrophage recruitment. Crucially, pharmacological interventions partially reversed these defects through mitochondrial support (CoQ10), acetylcholinesterase inhibition (Neostigmine), and targeted immune suppression (ML604440 for Th17 differentiation, GSK805 for Th17 function, and UNBS5162 for CXCL-related signaling). Together, these findings suggest that VARS2 links mitochondrial dysfunction to immune imbalance and neuromuscular injury in SNMG. Our study highlights mitochondrial immunometabolism as a candidate mechanistic axis and identifies VARS2 as a potential biomarker for SNMG-related immune remodeling.
    Keywords:  VARS2; immunometabolism; mitochondrial dysfunction; myasthenia gravis (MG); neuromuscular junction; seronegative myasthenia gravis (SNMG); zebrafish model
    DOI:  https://doi.org/10.3389/fimmu.2026.1861435
  34. J Immunol. 2026 Oct 01. pii: vkag234. [Epub ahead of print]215(10):
    Programmed cell death protein 1 (PD-1) regulates metabolic activity of regulatory T cells in ischemia-induced acute kidney injury.
    Oliver B Pelletier, Murat Dogan, Christopher O'Neill, Vikram Sabapathy, Didier Portilla, Rahul Sharma.
      Immune checkpoint inhibitor (ICPI) therapy, targeting Programmed cell death protein 1 (PD-1) and its ligands PD-L1 and PD-L2, have revolutionized cancer care. However, ICPI is linked to immune-related adverse events, including nephropathy manifesting as acute kidney injury (AKI), a rapid decline in kidney function, often progressing to renal failure. Regulatory T cells (Tregs) could mitigate AKI, caused by ischemia-reperfusion injury (IRI). Treg stability and function rely on cellular metabolism, with a distinct preference for oxidative phosphorylation (OXPHOS) over glycolysis. Although PD-1 is known to regulate metabolism of CD8 T cells, its role in controlling OXPHOS in Tregs remains underexplored. We demonstrate that PD-1 knockout (KO) mice have worse renal function after IRI when compared to wild-type mice. PD-1-deficient Tregs lose their protective ability against AKI despite retaining in vitro suppressive activity and Foxp3 expression. Transcriptomic analysis reveals altered expression of genes linked to function, proliferation, and mitochondrial metabolism in PD-1 KO Tregs as compared to wild-type Tregs. PD-1 KO Tregs exhibit reduced mitochondrial mass, membrane potential, biogenesis, and dynamics, leading to impaired mitochondrial fitness and trends for reduced expression of fatty acid transporters CD36 and Cpt1a and Glut1. Loss of PD-1 expression or antibody-mediated blockade of PD-1 attenuated OXPHOS and expression of genes related to mitochondrial metabolism in Tregs. These metabolic defects may stem from morphological alterations in mitochondria, highlighting the critical role of PD-1 in Treg-mediated nephroprotection. Our findings reveal the metabolic vulnerability of PD-1-deficient Tregs and underscore the importance of PD-1 in Treg-mediated protection against AKI with implications for ICPI-related nephropathy.
    Keywords:  AKI; PD-1; Treg; metabolism; mitochondria
    DOI:  https://doi.org/10.1093/jimmun/vkag234
  35. Small. 2026 Oct 08. e76147
    Iron-Metabolism-Modulating Carbon Dots Controllably Orchestrates Antibacterial and Immunoregulatory Synergy for Effective Bacterial Sepsis Therapy.
    Yao Wang, Peibo Liu, Chenyu Zhu, Debin Shen, Menghan Zhang, Ruilong Kou, Bin Lan, Hang Zhu, Jianyong Huang, Chengfei Zhao, Shaohuang Weng.
      Bacterial sepsis is a life-threatening condition marked by uncontrolled infection and immune dysregulation, in which iron metabolism critically influences pathogen proliferation and host inflammatory. Herein, we designed and synthesized functional diethylenetriaminepentaacetic acid-spermidine carbon dots (D-CDs), which exerted dual antibacterial and immunomodulatory effects by targeting iron metabolism. D-CDs exhibited high affinity for Fe3+, effectively chelating Fe3+ to induce "iron starvation" in bacteria, leading to metabolic disruption and increased oxidative stress, as evidenced by altered expression of gene associated with iron acquisition, energy metabolism, and oxidative stress defense. Furthermore, D-CDs displayed potent antibacterial activity against bacteria containing clinical isolated resistant strains. Concurrently, D-CDs protected host macrophages by attenuating ferroptosis through activation of the Nrf2/HMOX1 pathway and inhibition of the NF-κB pathway, thereby restoring redox balance and promoting polarization toward the anti-inflammatory M2 phenotype. In the two rat models of sepsis, induced by intravenous administration of bacterial suspension and by cecal ligation and puncture, D-CDs significantly improved survival rates, reduced systemic bacterial burden, and alleviated multi-organ inflammatory injury. Taken together, these findings suggest that iron metabolism centered modulation as a dual-targeting strategy possess brilliant future for treating severe bacterial infections through integrating antibacterial action with immune homeostasis.
    Keywords:  carbon dots; ferroptosis; integration of antibacterial and immunomodulatory abilities; iron metabolism; sepsis
    DOI:  https://doi.org/10.1002/smll.76147
  36. Cell Rep. 2026 Oct 05. pii: S2211-1247(26)01140-X. [Epub ahead of print]45(10): 118061
    Palmitate puts ACLY in shape to reprogram macrophages.
    Bin Huang, Chengqian Yin.
      Zhao et al.1 show that palmitate-driven ATP citrate lyase (ACLY) palmitoylation stabilizes nuclear ACLY tetramers, increases acetyl CoA production, and promotes pro-inflammatory macrophage programs. Targeting macrophage SCD1 with palmitate supplementation exploits this pathway to remodel the tumor microenvironment and suppress hepatocellular carcinoma.
    DOI:  https://doi.org/10.1016/j.celrep.2026.118061
  37. Eur J Immunol. 2026 Oct;56(10): e70278
    The Role of Sodium in Th17/Treg Immune Dysregulation and Autoimmunity.
    Vincent Driessen, Margarita Dominguez-Villar, David A Hafler, Markus Kleinewietfeld.
      Autoimmune diseases represent a major and growing health burden, particularly among young adults. Emerging evidence suggests that changes in the environment and diet may contribute to disease. Experimental studies have demonstrated that excessive salt intake can modulate immune function by inducing pathogenic pro-inflammatory T helper 17 cells (Th17) and impairing anti-inflammatory regulatory T cell (Treg) function both in vitro and in vivo, thereby promoting autoimmunity. Serum/glucocorticoid-regulated kinase 1 (SGK1) has been identified as a central mediator of immune function in response to high salt. Additionally, alterations in immunometabolism and epigenetic modulations have been linked to immune dysfunction under high-sodium conditions. Understanding the complex interplay between inflammatory processes, immunometabolism, and epigenetic regulation is essential for deciphering how ionic disturbances may shape T cell immunity and disease. Despite strong evidence from animal models linking sodium intake and shifts in the ionic microenvironment to immunomodulation and disease, evidence from human studies remains limited, largely due to small cohort sizes and methodological constraints. This review provides a comprehensive overview of sodium-induced immune alterations and underscores the need for larger and more standardized clinical studies to further clarify the role of sodium and changes in the ionic microenvironment in autoimmunity.
    DOI:  https://doi.org/10.1002/eji.70278
  38. Front Immunol. 2026 ;17 1916689
    Metabolic reprogramming, macrophage polarization, and intercellular crosstalk in pelvic inflammatory disease: emerging paradigms and therapeutic opportunities.
    Shangtao Liu, Tongyue Liu, YongTing Li, Suo Zhang, Qiumei Dong.
      Pelvic inflammatory disease (PID) is a condition caused by the ascension of pathogenic microorganisms from the lower genital tract to the uterus and/or fallopian tubes, and is one of the most common clinical syndromes among women of reproductive age. The long-term sequelae of PID, including chronic pelvic pain, infertility, and recurrent episodes, significantly impair patients' quality of life. However, the current clinical understanding of the immunopathological mechanism of PID remains insufficient, and there are no targeted therapeutic approaches. In recent years, macrophage polarization has been demonstrated to play a core regulatory role in the initiation, progression, and resolution of inflammation, and metabolic reprogramming is the key intrinsic mechanism driving the phenotypic transformation of macrophages, playing a crucial role in various diseases. At the same time, the bidirectional communication network between macrophages and endometrial cells has also been proven to play an important role in the disease progression. Therefore, clarifying the metabolic adaptation mechanism regulating macrophage polarization and its interaction with endometrial cells can provide potential targets for exploring new therapeutic strategies that target macrophage metabolism or block abnormal cell communication, which is crucial for developing targeted treatments that can restore immune homeostasis and alleviate the pathological damage of PID.
    Keywords:  inflammation; macrophage polarization; macrophages; metabolism; pelvic inflammatory disease
    DOI:  https://doi.org/10.3389/fimmu.2026.1916689
  39. Cell Rep. 2026 Oct 05. pii: S2211-1247(26)01157-5. [Epub ahead of print]45(10): 118078
    Differential formation of nitrate-responsive mycobacterial intracytoplasmic membranes during Mycobacterium tuberculosis infection.
    Camille Keck, Stéphane Tachon, Fadel Sayes, Daniele Musiani, Quentin Giai Gianetto, Mariette Matondo, Matthijn Vos, Roland Brosch, Jost Enninga.
      Subcellular compartmentalization of metabolic processes is a main feature of prokaryotic and eukaryotic architecture. Environmental bacteria generate intracytoplasmic membranes (ICMs) as a crucial strategy to adapt their metabolism to environmental changes. While pathogenic intracellular bacteria also perceive various stressful stimuli during host interactions, the subsequent re-organization of their internal architecture has not been explored. Using cryo-electron tomography, we show that Mycobacterium tuberculosis (Mtb), a major human pathogen, is able to form ICMs outside and inside host cells in a strain-dependent manner. We characterize these Mycobacterial intracytoplasmic Membranes (MIMs) as nitrate-induced structures. Furthermore, we uncover that MIM formation in Mtb during macrophage infection correlates with limited cellular inflammatory responses. Our findings reveal a cytoplasmic structure in Mtb and link it to a functional mechanism that enables the bacterium to adapt to its intracellular niche.
    Keywords:  CP: microbiology; Mycobacterium tuberculosis; cellular architecture; cryo-electron tomography; intracytoplasmic membranes; nitrate metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2026.118078
  40. Am J Transplant. 2026 Oct 06. pii: S1600-6135(26)02803-0. [Epub ahead of print]
    Mitochondrial pyruvate carrier inhibition restrains germinal center T follicular helper cells attenuating chronic graft-versus-host disease.
    Eun Ko, Fathima A Mohamed, Stephanie Y Rhee, Yujie Zhao, Rocio Amaro Marquez, Joanna Ly, Ethan G Aguilar, Haley Melin, Peter T Sage, Tanner Schumacher, Conor Ronayne, Angela Panoskaltsis-Mortari, Megan Riddle, Mark Osborn, Govindarajan Thangavelu, Peter A Crawford, Roddy S O'Connor, Michael C Zaiken, Keli L Hippen, Leslie S Kean, Jeffrey C Rathmell, Juan Liu, Jason W Locasale, Venkatram Mereddy, Bruce R Blazar.
      Chronic graft-versus-host disease (cGVHD) is a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. During cGVHD, T follicular helper cells (TFH) and germinal center B-cells (GCB) interactions produce pathogenic class-switched allo- and auto-antibodies. We utilized a multi-organ cGVHD mouse model with bronchiolitis obliterans (BO) to investigate TFH metabolism and metabolic vulnerabilities at early and late times post-transplant. We found that TFH were highly glycolytic early in cGVHD/BO progression but later transitioned to a more oxidative metabolic profile. The mitochondrial pyruvate carrier (MPC) transports pyruvate into the mitochondria, directly linking glycolysis to mitochondrial oxidative phosphorylation (OXPHOS). To disrupt the TFH glycolysis to OXPHOS transition that accompanies cGVHD/BO progression, we tested 7ACC2, a potent MPC inhibitor, in ex vivo and in vivo cGVHD-related assays. In a co-culture assay, 7ACC2 significantly reduced TFH:B dependent class-switched immunoglobulin production. In vivo, mice with established cGVHD/BO given 7ACC2 from days 28-49 significantly improved pulmonary function associated with lower TFH and GCB frequencies. Because MPC inhibitors are tested in clinical trials to treat metabolic diseases, cancer and neurodegenerative disease, clinical trials to test this novel MPC-based approach to stifle TFH metabolic demands in patients with treatment refractory cGVHD/BO progression warrants future consideration.
    Keywords:  Bronchiolitis Obliterans; Chronic graft-versus-host disease; T follicular helper cells; metabolic regulation
    DOI:  https://doi.org/10.1016/j.ajt.2026.09.041
  41. Food Chem Toxicol. 2026 Oct 08. pii: S0278-6915(26)00487-4. [Epub ahead of print] 116412
    An MMP12-Enriched Kupffer Cell-Associated Programme Links ATF3-Associated Immunometabolic Remodeling to Hepatic Metabolic Dysfunction and Fibrotic Communication Networks.
    Jing He, Wang Zhang, Pan-Pan Liu, Tian-Rong Pan.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of chronic liver injury, yet the cellular programmes linking metabolic stress with inflammation and fibrosis remain incompletely understood. Here, we integrated single-cell transcriptomics, regulatory network analysis, functional validation, and in vivo perturbation approaches to investigate macrophage-associated mechanisms during metabolic liver injury. We identified an MMP12-enriched Kupffer cell-associated programme that emerges under metabolic stress and exhibits distinct ATF3-associated immunometabolic characteristics. Functional modulation of ATF3 altered macrophage transcriptional states and mitochondrial metabolic properties, supporting its involvement in macrophage adaptation. Intercellular communication analysis combined with experimental validation identified CD93-associated hepatocyte responses and FLRT2-associated hepatic stellate cell activation as candidate pathways linking macrophage states with steatosis and fibrotic remodeling. Hepatic perturbation of these pathways improved metabolic and fibrosis-related phenotypes, while additional analyses defined the interpretation of AAV8-mediated effects at the hepatic pathway level rather than exclusive Kupffer cell specificity. Human liver datasets provided exploratory evidence for conservation of macrophage-associated regulatory programmes. Collectively, our findings reveal an immunometabolic framework connecting macrophage states with hepatic metabolic dysfunction and tissue remodeling, providing potential insights for precision therapeutic strategies in MASLD.
    Keywords:  Immunometabolic remodeling; Intercellular communication; Kupffer cells; MMP12-enriched macrophage programme; Macrophage heterogeneity; Metabolic dysfunction-associated steatotic liver disease (MASLD)
    DOI:  https://doi.org/10.1016/j.fct.2026.116412
  42. Front Immunol. 2026 ;17 1890366
    HDAC3-driven immunometabolic reprogramming in type 2 diabetes and its complications: from enzymatic deacetylation to non-enzymatic scaffolding.
    Nianxin Kang, Qiqi Zhang, Xiangyuan Zhang, Wenhao Cheng, Zezheng Gao, Tingting Bao, Linhua Zhao.
      Type 2 diabetes mellitus (T2DM) is driven by the intricate interplay between metabolic dysregulation and chronic inflammation. However, the comprehensive epigenetic mechanisms linking immune dysfunction to metabolic abnormalities remain incompletely understood. Histone deacetylase 3 (HDAC3), which possesses both deacetylase catalytic activity and non-enzymatic scaffold functions, has emerged as a critical regulator of immunometabolic homeostasis. Nevertheless, its coordinated pathogenic roles in T2DM and its multi-organ complications have not been fully elucidated. This review comprehensively integrates the regulatory mechanisms of HDAC3 in β-cell dysfunction, insulin resistance, mitochondrial impairment, and chronic inflammation, highlighting its pivotal role in the initiation and progression of T2DM. We further systematically summarize the shared pathogenic mechanisms mediated by HDAC3 in diabetic cardiomyopathy, nephropathy, retinopathy, encephalopathy, and impaired wound healing. In addition, we focus on precision therapeutic strategies targeting HDAC3, with particular emphasis on recent advances and translational challenges involving microRNAs (miR) and naturally derived HDAC3 inhibitors. Collectively, this review identifies HDAC3 as a central epigenetic hub underlying T2DM and its complications, providing novel mechanistic insights and a theoretical foundation for the development of precision-targeted therapies for diabetes and its associated complications.
    Keywords:  diabetic complications; epigenetic regulation; histone deacetylase 3; immunometabolism; type 2 diabetes
    DOI:  https://doi.org/10.3389/fimmu.2026.1890366
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