bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2026–10–11
forty-nine papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Peripheral dendritic cell priming of CD8+ T cells drives tau-related neurodegeneration.
  2. Cancer competition for vitamin B2 creates metabolic checkpoint for T cell ferroptosis.
  3. PRMT7 restricts CD8+ T cells expansion via the NF-ΚB pathway.
  4. Targeting hypoxia-driven histone lactylation in myeloid cells synergizes with CD137 agonism to expand effector-like exhausted CD8+ T cells in glioblastoma.
  5. Metabolic reprogramming of pathogenic CD4+ T helper cells attenuates inflammatory bowel disease in mice.
  6. Programmable CAR-engaging particles rewire human CAR T-cell signaling for sustainable ex vivo expansion.
  7. Sodium-Glucose Cotransporter SGLT2 Supports Metabolic Fitness and Ferroptosis Resistance in CAR-T Cells to Enhance Activity Against Solid Tumors.
  8. Protocol for analyzing tumor-infiltrating bystander CD8+ T cells in mice using adoptive transfer of P14 TCR-transgenic CD8+ T cells.
  9. Glutamine metabolism keeps pathogenic hepatic CD4+ T cells in check.
  10. Human filarial infection reshapes CD8+ T-cell transcription and function at homeostasis and following viral activation.
  11. Lymph node contraction links sex-biased naive CD8+ T cell decline to compromised antigen recognition during middle age.
  12. Pharmacologic HIF-2α inhibition preserves T cell effector function in clear cell renal cell carcinoma.
  13. Naive T cell decline limits cancer immunity in middle-aged male mice.
  14. Coordinated nicotinamide metabolism by NAMPT and NNMT: Integrating metabolic, epigenetic and immune crosstalk.
  15. Extracellular matrix-targeted TNC-scFv armoring enhances CAR T cell persistence and antitumor activity in solid tumors.
  16. SUMO2 deletion changes chromatin accessibility and enhances cytotoxic T cell activation and tumor infiltration.
  17. Automating chimeric antigen receptor T-cell manufacturing across distinct platforms delivers similar cell quality, phenotype and function.
  18. Advances in IL-2-based cancer immunotherapy and the synergistic role of stem-like CD8+ T cells in IL-2 and PD-1 combination therapy.
  19. Boosting CAR T cell efficacy in cancer with metabolic insights from design to diet.
  20. Why CD4+ T cells matter in adoptive cell therapy for solid cancers.
  21. Single-cell analyses of global cohorts outline determinants of immune aging and link the ratio of GZMK+ to GZMB+ Tem cells to health trajectories.
  22. Decoding the immune regulation of ovarian aging: mechanisms and therapeutic strategies.
  23. Enhanced antitumor efficacy through combined chimeric antigen receptor T cell therapy and CD40 stimulation in syngeneic solid tumor models.
  24. Epithelial SLC25A20 Deficiency Drives Immunosuppressive Neutrophil Remodeling via ARG1 Palmitoylation to Promote Colorectal Cancer.
  25. Non-enzymatic protein modifications at the interface of metabolism and immunity.
  26. Longitudinal multiomics reveals personalized aging trajectories.
  27. T cell dysfunction associated with repeated CAR-T cell manufacturing failure following prolonged bispecific antibody exposure: a case report.
  28. Lysine-specific demethylase 1 links metabolism to stemness in human neural stem cells.
  29. ANGPTL8 induces the aging of hematopoietic stem/progenitor cells.
  30. Clinically Meaningful or Just Measurable? What Physiologic Outcomes Tell Us About Aging Interventions.
  31. Restoring NAD+ pathways in brain aging and neurodegenerative diseases: roles of vitamin B3 metabolites, gut microbiota, and exercise in cognitive health.
  32. Antigen-experienced NK-T cells: integrating new insights and exploring therapeutic potential in cancer immunotherapy.
  33. Intrahepatic Tissue-Resident CD8+ T-Cell Programmes Associate With Fibrosis and Local Immune Remodelling in Autoimmune Hepatitis.
  34. LAG3 checkpoint function and its mechanism of action in therapeutic targeting.
  35. Targeting SLC38A5 Overcomes αPD-1 Immunotherapy Resistance by Alleviating Glutamine Competition Between Glioblastoma Cells and T Cells.
  36. Decline of chaperone-mediated autophagy in aging impairs macrophage clearance of senescent cells.
  37. Cellular senescence is associated with age-related loss of liver zonation and hepatocyte function.
  38. A developmentally restricted γδ T cell-IL-17A axis supports mouse heart regeneration.
  39. Arginine methylation in immunoregulation: Mechanisms and therapeutic targeting.
  40. Mitochondrial dysfunction as a metabolic checkpoint of immunotherapy response in colorectal cancer.
  41. Immunometabolic programming of macrophages and tumor-associated macrophages: metabolic pathways shaping polarization, immune regulation, and disease outcomes.
  42. KPNA2-Mediated MYC Nuclear Import Enhances CAR-T Cell Memory and Potentiates Antitumor Efficacy.
  43. Microbial cues and T cell immunity: deciphering their interactions in chronic liver disease.
  44. Inhibiting Glutaminase Reverses Senescence-Associated Mitochondrial Dysfunction and Skeletal Muscle Decline.
  45. Author Correction: Natural killer T cells and CD8+ T cells are dispensable for T cell-dependent allergic airway inflammation.
  46. Inhibition of CDK12/CDK13-CYCLIN K rewires P-TEFb signaling to reverse HIV-1 latency and modulate cellular gene expression.
  47. Reprogramming the myeloid-T cell ecosystem through engineered oncolytic viruses for durable antitumor immunity.
  48. Human T cell engineering via serial delivery of mRNA encapsulated within lipid nanoparticles.
  49. Chronic Senolytic Treatment and/or Aerobic Exercise Reduce Senescence and Improve Myocardial Function During Aging in the Heart.
  1. Nat Aging. 2026 Oct 07.
    Peripheral dendritic cell priming of CD8+ T cells drives tau-related neurodegeneration.
    Yahyah Aman.
      
    DOI:  https://doi.org/10.1038/s43587-026-01254-4
  2. 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
  3. Nat Commun. 2026 09 06. pii: 10564. [Epub ahead of print]17(1):
    PRMT7 restricts CD8+ T cells expansion via the NF-ΚB pathway.
    Nivine Srour, Kaixiu Luo, David Allard, Yan Xiong, Zhenbao Yu, Theodore Papadopoulos, François Santinon, Cheng-Hsun Hsieh, Anthony Parent, John Stagg, Simon Turcotte, Dalia Barsyte-Lovejoy, Stéphanie Lehoux, Sonia V Del Rincón, Jian Jin, Stéphane Richard.
      Successful cellular immunotherapy for cancer utilising cytotoxic T lymphocytes (CTL) requires efficient expansion while maintaining effector function. Understanding how CTL expansion and function are regulated during the cell preparation process is thus important. Here, we show that T cell-specific deletion of Prmt7 using CD4-Cre increases CD8+ T cell effector differentiation, cytokine secretion, cytolytic activity and anti-tumor responses. Prmt7 deficiency transcriptionally reprograms CD8+ T cells by activating the NF-κB pathway, boosting proliferation, and facilitating the production of effector molecules such as CD25, CD69 and IFNγ. Mechanistically, PRMT7 associates with RelA and restricts RelA nuclear translocation. In vitro, a self-developed PRMT7-targeting PROTAC degrader, MS54, similarly activates the NF-κB pathway as in Prmt7-deficient CTL. In vivo, adoptive cell transfer of MS54-treated OT-I CTLs improves tumor control in a mouse syngeneic melanoma model. In human CTL, MS54 enhances proliferation, activation markers (CD69, CD137) expression, IFNγ production and cytotoxicity toward melanoma. Our findings thus identify PRMT7 as a negative regulator of CD8+ T cell immunity and highlight MS54 as a potential strategy to improve adoptive T cell therapy.
    DOI:  https://doi.org/10.1038/s41467-026-77155-2
  4. Neuro Oncol. 2026 Oct 08. pii: noag226. [Epub ahead of print]
    Targeting hypoxia-driven histone lactylation in myeloid cells synergizes with CD137 agonism to expand effector-like exhausted CD8+ T cells in glioblastoma.
    Alessio Ugolini, Fabio Scirocchi, Alessandra De Leo, Filippo Badii, Xiaoxian Liu, Angelica Pace, Luca D'Angelo, James K C Liu, Arnold B Etame, Pulak Ray, Marianna Nuti, Antonio Santoro, Aurelia Rughetti, Michael A Vogelbaum, Xiaoqing Yu, Filippo Veglia.
       BACKGROUND: Overwhelming presence of immunoregulatory myeloid cells and dysfunctional T cells is a major barrier to effective immunotherapies in glioblastoma (GBM). Therapeutic strategies that simultaneously address myeloid-driven immunosuppression and impaired T cell function are therefore needed to restore antitumor immunity in GBM.
    METHODS: We employed single-cell RNA sequencing, immunophenotyping, and functional analyses in an orthotopic murine GBM model (SB28) to investigate how hypoxia shapes the tumor immune microenvironment and limits CD8+ T cell responses. Pharmacologic hypoxia modulation using low-dose axitinib was combined with therapeutic intervention targeting CD137 in two GBM models (SB28, CT2A).
    RESULTS: Monocyte-derived macrophages (MDMs) and neutrophils constitute the most abundant and functionally immunosuppressive myeloid subsets within the GBM TME. Hypoxia reprogrammed MDMs and neutrophils into immunosuppressive cells, limiting the expansion of CD8+ T cells. Low-dose axitinib reduced intratumoral hypoxia, leading to altered glucose uptake and histone lactylation in MDMs and neutrophils, thereby impairing their immunosuppressive function and promoting the expansion of intratumoral PD-1+CD137+CD8+ T cells, specifically in the SB28 model. CD137 is largely expressed by effector-like exhausted CD8+ T cell subsets (EX-eff). Agonistic targeting of CD137, in combination with axitinib, robustly expanded EX-eff, which was accompanied by durable tumor regression, immunological memory, and long-term survival. Additionally, the abundance of PD-1+CD137+CD8+ T cells correlated with improved disease-free survival in patients with GBM.
    CONCLUSION: Together, these findings establish a rationale for a combinatorial strategy that couples myeloid cells targeting and CD8+ T cell activation to overcome immunotherapy resistance in GBM.
    Keywords:  exhausted T cells; glioblastoma; histone lactylation; hypoxia; immunosuppressive myeloid cells
    DOI:  https://doi.org/10.1093/neuonc/noag226
  5. 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
  6. Nat Commun. 2026 09 07. pii: 10581. [Epub ahead of print]17(1):
    Programmable CAR-engaging particles rewire human CAR T-cell signaling for sustainable ex vivo expansion.
    Qinghe Zeng, Landon Flemming, Yuanzhou Chen, Thomas Mazumder, Heinz Hammerlindl, Greg M Allen, Ricardo Almeida, Jasper Z Williams, Rogelio A Hernández-López, Ania-Ariadna Baetica, Sara E Meyer, Joseph A Fraietta, Justin Eyquem, Chun J Ye, Wendell A Lim, Qizhi Tang, Tejal A Desai, Xiao Huang.
      T cell proliferative capacity and persistence determine the therapeutic efficacy of chimeric antigen receptor (CAR) T cells. However, strategies to externally enhance CAR-T cell expansion without genetic rewiring are lacking. Here, we engineer CAREp, programmable DNA-scaffolded PLGA microparticles displaying CAR-targeting antigens and CD28-costimulatory antibodies, to repeatedly stimulate human CD8+ CAR-T cells ex vivo. CAREp sustains a-EGFR CAR-T cell expansion for over 100 days across both 4-1BBζ and CD28ζ constructs, achieving up to 1018-fold cumulative expansion and surpassing tumor-cell or CD3/CD28-Dynabeads stimulation. Expanded cells retain effector function and mitochondrial fitness while exhibiting clonal enrichment, initially preserved memory-associated progenitor states, delayed exhaustion, and transiently activated telomerase delaying telomere attrition. Early transcriptomic responses show coordinated activation of DNA repair, chromatin remodeling, telomere maintenance, and mitochondrial function while restricting differentiation-associated signaling programs, mirroring long-term functional outcomes. These findings demonstrate that nanoscale ligand organization synchronizes acute CAR-T signaling with durable proliferative and metabolic states.
    DOI:  https://doi.org/10.1038/s41467-026-76570-9
  7. 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
  8. STAR Protoc. 2026 Oct 06. pii: S2666-1667(26)00539-3. [Epub ahead of print]7(4): 104886
    Protocol for analyzing tumor-infiltrating bystander CD8+ T cells in mice using adoptive transfer of P14 TCR-transgenic CD8+ T cells.
    Chunyang Xie, Wenwen Xi, Hairu Wang, Lilin Ye, Xiangyu Chen, Yao Lin.
      While tumor-specific CD8+ T cells become functionally exhausted within the tumor microenvironment (TME), virus-specific bystander memory CD8+ T (TBYS) cells are abundant and represent valuable immunotherapy targets. Here, we present a protocol to analyze tumor-infiltrating virus-specific TBYS cells in murine tumor models using P14 CD8+ T cells. We describe steps for monitoring long-term in vivo behavior of P14 TBYS cells and characterizing their differentiation trajectories and functional heterogeneity. For complete details on the use and execution of this protocol, please refer to Lin et al.1.
    Keywords:  Cancer; Cell isolation; Flow Cytometry; Immunology; Model Organisms
    DOI:  https://doi.org/10.1016/j.xpro.2026.104886
  9. 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
  10. JCI Insight. 2026 Oct 08. pii: e206042. [Epub ahead of print]
    Human filarial infection reshapes CD8+ T-cell transcription and function at homeostasis and following viral activation.
    Camila Queiroz-Glauss, Justin Lack, Daniel E Sturdevant, Thomas B Nutman.
      The role of CD8+ T cells in filarial infections remains poorly understood. Given the chronic nature of these infections, individuals living in endemic regions are frequently exposed to other pathogens including viruses. Because CD8 cells are essential for antiviral immunity, understanding how filarial infections shape the cytotoxic compartment is essential to elucidate their impact on bystander immunity. We evaluated the phenotype and function of CD8+ T cells from Loa loa-infected (Fil+) and -uninfected (Fil-) individuals at baseline and following cytomegalovirus (CMV) re-stimulation. Filarial infection was associated with increased activation and proliferation of CD8+ T cells, characterized by elevated expression of Ki-67, CD107a, and production of type 1 and 17 cytokines. Upon CMV re-stimulation, Fil+ individuals showed markedly reduced expansion of antigen-experienced (CD137+) and polyfunctional (CD137+IFN-γ+TNF-α+, CD137+IFN-γ+TNF-α+IL-2+) CD8+ T cells, along with decreased cytotoxic activity. Unbiased clustering analysis revealed markedly reduced frequency of the CD8+CD45RA+CD57+ subset in Fil+ individuals- a population further defined through transcriptomic profiling that showed enrichment for cytolytic gene signatures (GZMB, GNLY, GZMH, CD244, CX3CR1). These results demonstrated that filarial infection is associated with an altered CD8+ T cell profile that is associated with failure to mount effective viral-specific effector responses, including impaired cytokine production and cytotoxic activity.
    Keywords:  Adaptive immunity; Cellular immune response; Immunology; Infectious disease; Public Health; T cells
    DOI:  https://doi.org/10.1172/jci.insight.206042
  11. Nat Aging. 2026 Oct 09.
    Lymph node contraction links sex-biased naive CD8+ T cell decline to compromised antigen recognition during middle age.
    Lutz Menzel, Maria Zschummel, Meghan J O'Melia, Mårten Sandstedt, Hengbo Zhou, Pin-Ji Lei, Lingshan Liu, Hang Lee, Debattama R Sen, Lance L Munn, Lena Jonasson, Timothy P Padera.
      The abundance of diverse naive CD8+ T cell clones is essential for broad protection against infection and cancer, but how sex and aging jointly shape this compartment remains poorly understood. Here, using mouse models with supporting human data, we uncover a sex-biased mechanism of immune aging in which early male-biased depletion of naive CD8+ T cells driven by accelerated, antigen-agnostic differentiation into virtual memory cells combines with thymic involution, limiting naive CD8+ T cell replenishment. These mechanisms led to more rapid lymph node contraction and reduced local naive T cell clone availability in males, limiting cancer antigen recognition. Therapeutic thymus regeneration via androgen ablation repopulated naive CD8+ T cells in lymph nodes, reinvigorated cancer-specific T cell responses and enhanced responsiveness to immune checkpoint blockade in male mice. These findings reveal the impact of sex and age on naive T cell clone abundance in lymph nodes and suggest strategies to restore immune competence in middle-aged men.
    DOI:  https://doi.org/10.1038/s43587-026-01238-4
  12. J Clin Invest. 2026 Oct 06. pii: e204613. [Epub ahead of print]
    Pharmacologic HIF-2α inhibition preserves T cell effector function in clear cell renal cell carcinoma.
    Katrine N Madsen, Soki Kashima, Hanna Soulati, Lena Wirth, Katsuhiro Ito, Zachary A Yochum, Vivien Moritz, Julia Walker, Marc Machaalani, Fady Ghali, Patrick Kenney, Adebowale Adeniran, Michael Hurwitz, Toni K Choueiri, David A Braun.
      Hypoxia-inducible factor 2α (HIF-2α) is a central oncogenic driver in clear cell renal cell carcinoma (ccRCC) and a therapeutic target of the small-molecule inhibitor belzutifan. Genetic studies in murine models have suggested that hypoxia signaling may support T cell effector programs, raising concern that HIF-2α inhibition could impair antitumor immunity. However, whether pharmacologic HIF-2α inhibition alters human T cell biology remains unknown. Here, we investigated the cell-intrinsic effects of EPAS1 (encoding HIF-2α) perturbation in primary human T cells. CRISPR/Cas9-mediated deletion of HIF-2α demonstrated no notable transcriptional effects. Similarly, pharmacologic treatment with belzutifan produced minimal transcriptional changes and did not impair proliferation, cytokine production, polyfunctionality, or cytotoxic activity in T cells derived from healthy donor peripheral blood, peripheral blood from patients with ccRCC, or tumor-infiltrating lymphocytes under hypoxic conditions. High- dimensional immunophenotyping revealed preserved T cell differentiation and activation states following pharmacologic HIF-2α inhibition in vitro and in peripheral blood from patients receiving HIF-2α inhibitor therapy. Together, these findings demonstrate that pharmacologic HIF-2α inhibition preserves key effector programs, providing a mechanistic basis for the immunologic safety of HIF-2α-targeted therapy in ccRCC.
    Keywords:  Cancer; Hypoxia; Immunology; Oncology; T cells
    DOI:  https://doi.org/10.1172/JCI204613
  13. Nat Aging. 2026 Oct 09.
    Naive T cell decline limits cancer immunity in middle-aged male mice.
      
    DOI:  https://doi.org/10.1038/s43587-026-01239-3
  14. 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
  15. Sci Adv. 2026 Oct 09. 12(41): eaeh3957
    Extracellular matrix-targeted TNC-scFv armoring enhances CAR T cell persistence and antitumor activity in solid tumors.
    Kaizhao Chen, Qi Fu, Wei Zhang, Ziyang Lin, Longjun Chen, Youxi Zhou, Yongkun Huo, Ziqing Gao, Haoyang Wan, Caifang Wang, Xingxu Huang, Shuaishuai Zhang, Ming Liu, Xiaodong Ma.
      Chimeric antigen receptor T cell (CAR T cell) therapy has shown limited efficacy in solid tumors, largely due to physical and immunosuppressive barriers imposed by the tumor microenvironment (TME). Tenascin-C (TNC), an extracellular matrix protein highly expressed in multiple solid malignancies, contributes to immune exclusion and T cell dysfunction. Here, we engineer an armored CAR T cell platform that locally targets the extracellular matrix by secreting a TNC-specific single-chain variable fragment (TNC-scFv) linked to conventional CAR architecture. TNC-scFv-armored CAR T cells exhibit enhanced cytotoxic activity, improved persistence, and reduced exhaustion in vitro and in xenograft tumor models. Single-cell transcriptomic analysis reveals that TNC targeting reprograms the TME toward a CD8+ T cell-enriched and functionally active immune landscape. In humanized tumor models, TNC-scFv-armored CAR T cells mediate robust antitumor responses with minimal systemic toxicity. This extracellular matrix-targeted armoring framework is compatible with additional immunomodulatory payloads, as illustrated by combinatorial armoring with interleukin-2, which further enhances efficacy while mitigating cytokine-associated toxicity. Together, these results establish extracellular matrix-directed armoring as a generalizable strategy to improve CAR T cell therapy for solid tumors.
    DOI:  https://doi.org/10.1126/sciadv.aeh3957
  16. Sci Adv. 2026 Oct 09. 12(41): eaef2217
    SUMO2 deletion changes chromatin accessibility and enhances cytotoxic T cell activation and tumor infiltration.
    Mohottige D Neranjan Tharuka, Dai-Hua Chen, Maria Luisa Jurgensen Amaral, Tianchen Ren, Yixuan Kuang, Shih-Ting Huang, Nikhil Chilakapati, Bing Ren, Stephen P Schoenberger, Ye Zheng, Yuan Chen.
      Cytotoxic T cells [cytotoxic lymphocytes (CTLs)] are crucial for adaptive immunity leading to prolonged survival and potential cures for cancer. Recent clinical data have shown that pharmacological inhibition modifies the tumor microenvironment (TME) and activates CTLs, although the mechanism is not well described. In this study, we found that T cell-specific knockout (KO) of the most prevalent SUMO paralog, Sumo2/SUMO2, in both mouse and human CD8+ T cells significantly enhanced CD8+ T cell activation without enhanced IFN-I (type I interferon)-responsive genes in vitro but increased chromatin accessibility at enhancer regions for AP-1 (activating protein 1) family members, including BATF and JunB, which are known to promote T cell activation and proliferation. Using antigen-specific OT1 and CAR (chimeric antigen receptor) T cell models, we found that Sumo2 KO CD8+ T cells had significantly higher tumor infiltration, as revealed by flow cytometry, immunofluorescence staining, and single-nucleus RNA sequencing (snRNA-seq), and conferred greater tumor growth inhibition than wild-type control T cells. snRNA-seq also revealed that Sumo2 KO in CD8+ T cells increased the expression of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) in vivo and activated the antitumor immune microenvironment, likely through cell-cell interaction involving more activated CTLs. These findings elucidate a novel mechanism by which SUMOylation controls CTL activation and tumor infiltration that activate antitumor immunity in the TME. SUMO2 KO can also be a potential strategy to enhance adoptive T cell therapies for solid tumors by enhancing their activation, tumor infiltration and ability to modulate the TME.
    DOI:  https://doi.org/10.1126/sciadv.aef2217
  17. Cytotherapy. 2026 Aug 05. pii: S1465-3249(26)00939-4. [Epub ahead of print]28(12): 102978
    Automating chimeric antigen receptor T-cell manufacturing across distinct platforms delivers similar cell quality, phenotype and function.
    Eu Han Lee, Meredith Safford, Terri Staab, Min Sung Park, Mack Ryan, Despina Pleitez, Alex Sargent.
       BACKGROUND AIMS: Manufacturing chimeric antigen receptor (CAR) T cell therapies is complex and costly, and automation holds tremendous promise to improve access to these life-saving treatments.
    METHODS: Here, we compared two end-to-end automated CAR T-cell manufacturing platforms, the CliniMACS Prodigy and the Sefia system, using identical reagents, stimulation conditions, culture duration, perfusion rate and donor starting material to assess how platform design affects critical product attributes.
    RESULTS: With identical CD4 and CD8 magnetic isolation reagents, both systems produced similar T-cell yields, with exceptionally high purity and comparable phenotype. During culture, total cell yield differed between platforms, reflecting differences in culture volume; however, expansion rate, population doubling time, transduction efficiency and CAR T-cell yield were not significantly different. The resulting CAR T cells also showed comparable phenotype, exhaustion profiles and in vitro tumor-killing activity. These similar outcomes may be explained by shared media perfusion rates and convergent metabolic profiles, because cell-specific glucose consumption and cell-specific lactate production were similar by the end of culture.
    CONCLUSIONS: Collectively, these findings show that distinct automated platforms can generate CAR T-cell products with remarkably similar quality and function when process conditions are aligned. More broadly, they highlight the potential of automation and in-line analytics to standardize CAR T cell manufacturing and improve product consistency from cell collection to patient infusion.
    Keywords:  CAR T cell; T cell; automation; cell therapy
    DOI:  https://doi.org/10.1016/j.jcyt.2026.102978
  18. Front Immunol. 2026 ;17 1756987
    Advances in IL-2-based cancer immunotherapy and the synergistic role of stem-like CD8+ T cells in IL-2 and PD-1 combination therapy.
    Huiquan Gao, Shubo Wang, Huiru Yuan, Bingxiu Zhou, Fuxin Zhou.
      IL-2 is a pleiotropic cytokine that plays a central role in the activation and proliferation of cytotoxic lymphocytes and regulatory T cells. Since its discovery in 1976 as a T-cell growth factor and its subsequent U.S. FDA approval for metastatic renal cell carcinoma and melanoma, IL-2 has represented a landmark in cancer immunotherapy. However, high-dose (HD) IL-2 therapy is associated with substantial toxicities, including vascular leak syndrome. Recent advances in structural and receptor biology have clarified the molecular mechanisms underlying IL-2's dual immunostimulatory and immunoregulatory effects. These discoveries have enabled the design of next-generation IL-2 variants (IL-2v) with improved pharmacokinetics, receptor selectivity, and safety profiles. Importantly, PD-1+ TCF-1+ stem-like CD8+ T cells have recently been identified as a key population sustaining long-term antitumor immunity. TCF-1 is a transcription factor associated with a less differentiated, self-renewing state and marks this progenitor-exhausted subset. By contrast, terminally exhausted T cells exhibit a highly differentiated, poorly proliferative state and limited capacity for functional reinvigoration, whereas progenitor-exhausted cells retain stem-like properties, self-renewal capacity, and responsiveness to therapy. Furthermore, these cells respond robustly to IL-2 and are central mediators of the synergy observed between IL-2 signaling and PD-1 blockade. Mechanistically, PD-1 inhibition releases inhibitory constraints, while IL-2 provides a potent STAT5-driven proliferative and differentiation signal that expands the stem-like CD8+ T-cell pool and generates functional effector CD8+ T cells. This review summarizes IL-2 biology, the limitations of high-dose IL-2 (HD IL-2) therapy, and emerging strategies, including CD25- or CD122-biased IL-2 variants, tumor-targeted IL-2 prodrugs, and IL-2-based combination therapies designed to harness IL-2's antitumor potential while minimizing systemic toxicity, with particular emphasis on the role of stem-like CD8+ T cells as key mediators of therapeutic efficacy.
    Keywords:  CD122 bias; CD25 bias; IL–2; IL–2 variants; cancer immunotherapy; cytokine engineering; immunocytokines; prodrugs of IL–2
    DOI:  https://doi.org/10.3389/fimmu.2026.1756987
  19. 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
  20. Immunooncol Technol. 2026 Dec;32 101615
    Why CD4+ T cells matter in adoptive cell therapy for solid cancers.
    S Jegatheeson, C Scheffler, M De Bondt, P K Darcy, P J Neeson.
      Cytotoxic CD8+ T cells have been the focus of research efforts to improve the efficacy of anticancer adoptive cell therapies. However, emerging evidence is highlighting the critical role of CD4+ T cells in these treatments, including chimeric antigen receptor-T cells. Although the presence of CD4+ T cells is known to be important for efficacy of cell therapies, the mechanisms by which CD4+ chimeric antigen receptor-T cells exert their beneficial effects remain incompletely understood. In this article, we review the roles of CD4+ T cells in adoptive cell therapy, highlighting understudied areas that are yet to be explored, and propose new directions to advance our understanding of their antitumour potential.
    Keywords:  CD4+ T cells; T cell receptor; adoptive therapy; chimeric antigen receptor T cells; solid cancers; tumor infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/j.iotech.2026.101615
  21. Immunity. 2026 Oct 09. pii: S1074-7613(26)00387-0. [Epub ahead of print]
    Single-cell analyses of global cohorts outline determinants of immune aging and link the ratio of GZMK+ to GZMB+ Tem cells to health trajectories.
    Marina Terekhova, Maksim Kleverov, Thomas Francis, Dmitrii Usoltsev, Pavla Bohacova, Laura Arthur, Petr Tsurinov, Denis Kleverov, Luke Trinity, Kamila Husarcikova, Ivan Molotkov, Titas Grabauskas, Amir Fathi, Eloise Milbourn, Esme Newton, Leah Siegel, Adnaan Ghanchi, Urika Tse, Ross D Pollock, Niharika A Duggal, Janet M Lord, Norman R Lazarus, Ali H Ellebedy, Duygu Ucar, Stephen D R Harridge, Mykyta Artomov, Maxim N Artyomov.
      Human immune aging is heterogeneous, with immune responses becoming increasingly variable over the lifespan. Here, we integrated seven large-scale public single-cell peripheral blood mononuclear cell (PBMC) datasets and a newly generated cohort, encompassing 2,609 ostensibly healthy individuals across diverse ages, ancestries, and biological sexes. We identified both conserved and cohort-associated age-associated remodeling across 59 immune populations, together with sex- and ancestry-dependent immune differences. CD8+ T cells emerged as major drivers of aging heterogeneity, with the GZMK+/GZMB+ effector memory ratio distinguishing healthy and pathology-associated aging trajectories. This ratio reflected immune remodeling driven by chronic viral exposure, including CMV, and disease-associated immune dysregulation, with the dominant driver varying across populations. Proteomic profiling across four cohorts revealed a Tem GZMB+ plasma signature associated with inflammaging, poor self-reported health, all-cause mortality, and increased risk of immune-related, metabolic, and cardiovascular diseases. Together, these findings define clinically relevant immune determinants for monitoring and guiding healthy aging interventions.
    Keywords:  CD8(+) Tem GZMB(+); CD8(+) Tem GZMK(+); immune aging; proteomics; single cell
    DOI:  https://doi.org/10.1016/j.immuni.2026.09.012
  22. Hum Reprod Update. 2026 Oct 09. pii: dmag030. [Epub ahead of print]
    Decoding the immune regulation of ovarian aging: mechanisms and therapeutic strategies.
    Changjing Wang, Nianyu Li, Zi-Jiang Chen, Yingying Qin, Xue Jiao.
       BACKGROUND: Ovarian aging is among the earliest functional declines in humans and acts as a pacemaker of female aging. It encompasses both physiological age-related ovarian decline and pathological accelerated aging, exemplified by premature ovarian insufficiency (POI). Increasing evidence positions the immune system as both a regulator of ovarian homeostasis and a driver of ovarian dysfunction. Age-related immunosenescence and chronic low-grade inflammation (inflammaging) coordinately drive ovarian aging through bidirectional crosstalk between systemic immunity and the ovarian immune microenvironment. POI frequently coexists with autoimmune disorders, reinforcing the central role of the immune-ovarian axis in reproductive aging. Elucidating this interplay may enable targeted immunomodulatory strategies to preserve reproductive longevity and mitigate systemic consequences of ovarian decline.
    OBJECTIVE AND RATIONALE: The aim was to synthesize current evidence on (i) immune regulation of normal ovarian physiology; (ii) immune alterations in physiological ovarian aging, including systemic immunosenescence and ovarian immune microenvironment remodelling; (iii) autoimmune dysregulation in POI; and (iv) the translational potential of immunomodulatory interventions for mitigating ovarian aging.
    SEARCH METHODS: Original articles published up to April 2026 were identified through PubMed using combinations of the terms 'immune system', 'ovarian function', 'inflammation', 'immune cell', 'ovarian aging', 'menopause', 'primary ovarian insufficiency', and 'therapeutics'.
    OUTCOMES: Immune cells and cytokine networks form a specialized regulatory axis that governs folliculogenesis, ovulation, and luteal dynamics. This review synthesizes emerging evidence showing that this immune-ovary axis undergoes profound remodelling during reproductive aging and that immune dysregulation is a causal driver of ovarian functional decline. Systemically, the menopausal transition accelerates immunosenescence and amplifies pro-inflammatory cytokine production. Locally, the aging ovary exhibits chronic inflammation, NLRP3 inflammasome activation, and accumulation of senescent cells with a senescence‑associated secretory phenotype. These changes coincide with a shift from tissue‑resident to monocyte‑derived macrophages and expansion of inflammatory γδ and double‑negative T cells. This progressive loss of immune homeostasis promotes follicular depletion, stromal fibrosis, and impaired steroidogenesis. POI represents a pathological extreme of this axis, characterized by autoimmune comorbidities, B cell-driven humoural abnormalities, T cell dysregulation, and genetic variants affecting immune pathways. Comparative analysis reveals both conserved inflammatory signatures shared with physiological aging and POI-specific immune features that reflect overt immune-mediated ovarian injury. By integrating systemic, local, and disease-specific immune mechanisms, this review reframes ovarian aging as a modifiable immunological process. Therapeutically, emerging immunomodulatory strategies range from molecular agents targeting inflammatory mediators and senescence programs, through cell-based immune reprogramming with stem cells, regulatory T cells, and senolytic immune effectors, to lifestyle-driven systemic immunomodulation. These strategies show promise in restoring ovarian immune homeostasis and extending the reproductive lifespan, with several of these approaches now advancing toward early-phase clinical evaluation.
    WIDER IMPLICATIONS: Collectively, the current evidence positions immune dysregulation as a mechanistic driver, rather than a secondary correlate, of ovarian aging. Integrating immune biomarkers into predictive frameworks and designing stratified immunomodulatory trials may shift ovarian aging management from symptomatic hormone replacement toward mechanism-based intervention. Reframing ovarian aging as a modifiable immune-mediated process offers new opportunities to extend female reproductive longevity and the female health span.
    REGISTRATION NUMBER: N/A.
    Keywords:  immune cell; immune system; inflammation; menopause; ovarian aging; ovarian function; premature ovarian insufficiency; therapeutics
    DOI:  https://doi.org/10.1093/humupd/dmag030
  23. Cytotherapy. 2026 Aug 06. pii: S1465-3249(26)00938-2. [Epub ahead of print]28(12): 102977
    Enhanced antitumor efficacy through combined chimeric antigen receptor T cell therapy and CD40 stimulation in syngeneic solid tumor models.
    Giulia Golinelli, Ting-Jia Fan, Khatuna Gabunia, Wesley V Wilson, Charles-Antoine Assenmacher, He N Xu, Diego Gonzalves, Sofia Castelli, Jordan Reff, David Mai, Omar Johnson, Zachary Ferraro, Aasha Gupta, Mansi Deshmukh, Deeksha Muthumani, Decheng Song, Daniel Martinez, Enrico Radaelli, Jillian Verrelle, Federica Masciotta, Valentino Santori, Shimin Liu, Julia Tchou, Massimo Dominici, Regina M Young, Andrew J Rech, Carl H June, John Scholler, Bruce L Levine.
       BACKGROUND: Solid tumors present unique barriers to treatment with chimeric antigen receptor (CAR) T cells, including poor tumor infiltration into a highly immunosuppressive and metabolically challenging tumor microenvironment (TME).
    OBJECTIVES: To enhance both CAR T cell efficacy and the overall immune response against solid tumors, this study explored the therapeutic potential of combining CAR T cells with CD40 stimulation via an agonistic CD40 antibody (αCD40). We hypothesized that CAR T cells could serve as targeted vaccines, promoting antigen release and cooperating with αCD40 to activate and mobilize the endogenous immune cells, thus "heating up" the TME and potentially rendering it more receptive to subsequent therapies.
    METHODS: We used a syngeneic mouse model of pancreatic ductal adenocarcinoma and further validated our findings in a triple-negative breast cancer mouse model RESULTS: This combined strategy was associated with enhanced antitumor activity over CAR T cells alone. This included rapid and sustained tumor necrosis, increased immune cell activation both systemically and within the TME, as well as an overall improvement in survival rates. Comprehensive immune profiling at early time points revealed mechanistic insights into the enhanced antitumor effects of CAR T cell therapy and αCD40 treatment.
    CONCLUSIONS: These findings set the stage for future clinical applications of CAR T cells in combination with CD40 agonists for the treatment of challenging solid tumors.
    Keywords:  CAR T; CAR T cell therapy; CD40; T cell; immunotherapy; solid tumors
    DOI:  https://doi.org/10.1016/j.jcyt.2026.102977
  24. Adv Sci (Weinh). 2026 Oct 04. e78114
    Epithelial SLC25A20 Deficiency Drives Immunosuppressive Neutrophil Remodeling via ARG1 Palmitoylation to Promote Colorectal Cancer.
    Yue Han, Tian-Yuan Tan, Bin Zhang, Ye-Bin Fu, Wen Chen, Min-Hui Yang, Yi-Qing Wang, Yan-Qing Ding, Shuang Wang.
      While lipid metabolic reprogramming is increasingly recognized as a substantial driver of tumor microenvironment (TME) remodeling, how dysregulated fatty acid oxidation (FAO) contributes to immune evasion in colorectal cancer (CRC) progression remains obscure. Here, we identify the mitochondrial carnitine-acylcarnitine translocase solute carrier 25 member 20 (SLC25A20), an essential conduit for FAO, as a key regulator of CRC progression through neutrophil phenotypic remodel. Mechanistically, SLC25A20 deficiency in CRC cells blunts mitochondrial long-chain fatty acid (LCFA) import and FAO, triggering the release of LCFAs into the TME. This lipid-rich niche not only vigorously recruits tumor-associated neutrophils (TANs), but intrinsically programs them toward an immunosuppressive phenotype. Specifically, tumor-derived LCFAs enforce arginase-1 (ARG1) protein stability in TANs via ZDHHC18-mediated palmitoylation. This distinct post-translational modification (PTM) is indispensable for TAN-mediated CD8+ T cell suppression and subsequent tumor immune evasion. Importantly, genetic or pharmacological blockade of this palmitoylation axis in TANs reinvigorates antitumor immunity and abolishes the tumor-promoting effects of SLC25A20 deficiency. Collectively, our findings uncover a novel lipid-driven metabolic symbiosis between CRC and neutrophils, highlighting the ZDHHC18-ARG1 palmitoylation axis as a promising therapeutic strategy for CRC intervention.
    Keywords:  colorectal cancer; metabolic reprogramming; metastasis; palmitoylation; solute carrier family member 20; tumor‐associated neutrophils
    DOI:  https://doi.org/10.1002/advs.78114
  25. 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
  26. Nat Aging. 2026 Oct 06.
    Longitudinal multiomics reveals personalized aging trajectories.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-026-01248-2
  27. Leuk Res Rep. 2026 ;26 100611
    T cell dysfunction associated with repeated CAR-T cell manufacturing failure following prolonged bispecific antibody exposure: a case report.
    Skylar J W Henry, Kirsten Pfeffer, Kevin G Shim, Erin W Meermeier, Fan Feng, Julia E Wiedmeier, Saurabh Chhabra, P Leif Bergsagel, Rafael Fonseca, Alex M Wonnaparhown, Michael P Gustafson.
       Overview: We describe a patient with two consecutive manufacturing failures after prolonged bispecific antibody treatment in which longitudinal immune phenotyping and functional assays were performed to investigate potential mechanisms.
    Background: CAR-T cell therapy and bispecific antibodies (BsAb) have significantly improved outcomes in relapsed/refractory multiple myeloma (r/rMM), yet the optimal treatment sequence remains unclear, particularly regarding the impact of prior BsAb exposure on downstream CAR-T manufacturability.
    Case Presentation: A 72-year-old man with r/rMM had two CAR-T cell manufacturing failure events following multiple therapies including an FcRL5 × CD3 bispecific antibody. Both collections yielded an insufficient CAR-T cell dose. Longitudinal immune phenotyping revealed markers of T cell dysfunction, including loss of CCR7, CD27, and CD28, alongside severely impaired TCR-driven proliferation with preserved interleukin-2 responsiveness.
    Conclusion: These findings link profound T cell dysfunction with repeated CAR-T cell manufacturing failures and suggest that pre-leukapheresis immune phenotyping may identify patients at risk for manufacturing failure.
    Keywords:  Bispecific antibody; CAR-T cell therapy; Case report; T cell dysfunction
    DOI:  https://doi.org/10.1016/j.lrr.2026.100611
  28. Stem Cell Reports. 2026 Oct 08. pii: S2213-6711(26)00326-7. [Epub ahead of print] 103115
    Lysine-specific demethylase 1 links metabolism to stemness in human neural stem cells.
    Kazutoshi Murotomi, Kazumi Hirano, Kazutaka Araki, Hiroko Ishitsuka, Daisuke Miura, Shinjiro Hino, Masakazu Namihira.
      Epigenetic regulation of stem cell fate requires tight coordination with cellular metabolism; however, key downstream effectors remain poorly defined. Here, we show that lysine-specific demethylase 1 (LSD1) governs metabolic programs essential for stemness in human fetal neural stem cells. LSD1 inhibition induced a pronounced glycolytic shift accompanied by altered lineage commitment, characterized by suppression of neuronal differentiation and promotion of astrocytic fate. Machine learning-based Elastic Net analysis of transcriptomic data identified a subset of metabolic genes, including PLPP2 and CPT1A, which regulate phospholipid metabolism and mitochondrial fatty acid oxidation, as key downstream effectors of LSD1. Functional perturbation experiments showed that knockdown of these candidates attenuated LSD1 inhibition-induced glycolytic activation and ameliorated distinct differentiation phenotypes. Chromatin immunoprecipitation sequencing revealed LSD1 occupancy at metabolic gene loci, supporting their transcriptional repression by LSD1. Together, these findings identify LSD1 as an epigenetic gatekeeper preserving stemness by restraining glycolysis and inappropriate lineage commitment.
    Keywords:  LSD1; epigenetic regulation; glycolysis; machine learning; metabolic reprogramming; neural stem cells; neuronal differentiation
    DOI:  https://doi.org/10.1016/j.stemcr.2026.103115
  29. Biogerontology. 2026 Oct 08. pii: 174. [Epub ahead of print]27(5):
    ANGPTL8 induces the aging of hematopoietic stem/progenitor cells.
    Meijuan Chen, Min Zhang, Hanyi Mei, Xinyu Bai, Xiaoli Wang, Yijun Tang, Hua Jiang, Lulu Zhang, Chunfang Zhou, Yahong Yuan.
      Hematopoiesis depends on the sustained function of hematopoietic stem and progenitor cells (HSPCs). However, aging progressively impairs HSPC function, contributing to immunosenescence, hematologic malignancies, and degenerative disorders. Therefore, elucidating the mechanisms underlying HSPC aging is essential for developing strategies to alleviate age-related dysfunction. Here, we identify angiopoietin-like 8 (ANGPTL8), a secreted glycoprotein known for its role in glucose and lipid metabolism, as a novel regulator of HSPC aging. Systemic ANGPTL8 knockout significantly attenuated senescence-associated phenotypes in multiple murine tissues. In vitro and in vivo analyses of proliferation, colony-forming capacity, mitochondrial membrane potential, senescence-associated secretory phenotype (SASP) expression, reactive oxygen species (ROS) accumulation, myeloid skewing, and early hematopoietic regeneration further demonstrated that ANGPTL8 promotes HSPC aging. Mechanistically, ANGPTL8 deficiency activated the PI3K/AKT signaling pathway, whereas a PI3K activator rescued the senescence effects induced by recombinant ANGPTL8 (rANGPTL8). Furthermore, co-immunoprecipitation (Co-IP) confirmed that rANGPTL8 directly interacts with the transmembrane receptor PirB. Recombinant PirB (rPirB) reduced the phosphorylation of PI3K/AKT, whereas PirB knockdown effectively blocked the inhibitory effect of rANGPTL8 on PI3K/AKT phosphorylation. Collectively, our findings suggest that ANGPTL8 drives HSPC aging primarily by suppressing the PI3K/AKT pathway via its receptor PirB, providing a new potential target to alleviate the aging of HSPCs.
    Keywords:  ANGPTL8; Aging; Hematopoietic stem/progenitor cells; PI3K/AKT; Senescence-associated secretory phenotype
    DOI:  https://doi.org/10.1007/s10522-026-10517-x
  30. Curr Geriatr Rep. 2025 Dec;pii: 15. [Epub ahead of print]14(1):
    Clinically Meaningful or Just Measurable? What Physiologic Outcomes Tell Us About Aging Interventions.
    Brittany Butts, Christopher Herring, Chloe Park, Enid Swatson, Jordan Watson, Whitney Wharton.
       Purpose of review: As the aging population grows, identifying interventions that meaningfully improve physiologic health is increasingly important. This review examines recent evidence (2019-2025) on exercise, nutrition, pharmacologic, and multimodal interventions aimed at preserving function and extending healthspan in adults aged ≥65 years.
    Recent findings: Exercise and protein supplementation-particularly when combined-consistently improve muscle strength, mobility, and cardiovascular fitness. Multidomain lifestyle programs delay disability and enhance physical function. Novel approaches, including pharmaconutrition, senolytics, and stem cell therapies, target aging processes such as inflammation, cellular senescence, and sarcopenia. These early-phase interventions show promise for improving strength, reducing frailty, and potentially slowing biological aging.
    Summary: Targeted interventions can improve physiologic outcomes and functional status in older adults. Lifestyle strategies remain foundational, while emerging geroscience-based therapies may offer additive benefits. Future research should clarify optimal combinations, timing, and patient selection to guide personalized, integrative approaches to healthy aging.
    Keywords:  exercise interventions; frailty prevention; geroscience therapies; nutritional supplementation; older adults; physiologic outcomes
    DOI:  https://doi.org/10.1007/s13670-025-00435-0
  31. Front Nutr. 2026 ;13 1865556
    Restoring NAD+ pathways in brain aging and neurodegenerative diseases: roles of vitamin B3 metabolites, gut microbiota, and exercise in cognitive health.
    Wu Zhang.
      Aging and neurodegenerative disorders (NDDs) are intricately linked to a gradual deterioration in nicotinamide adenine dinucleotide (NAD+) metabolism, compromised mitochondrial functionality, persistent inflammation, and modified gut-brain interactions. Derivatives of vitamin B3, such as niacin, nicotinamide, nicotinamide riboside, and nicotinamide mononucleotide, have been identified as pivotal NAD+ precursors that possess the potential to support cellular bioenergetic processes and modulate pathways associated with brain aging. Evidence from preclinical studies and emerging clinical investigations suggests that NAD+-enhancing interventions may improve mitochondrial function and modulate neuroinflammatory pathways, thereby supporting cellular processes involved in synaptic plasticity and cognitive function; however, their long-term efficacy and clinical relevance in NDDs remain to be fully established. Concurrently, physical exercise serves as a robust physiological stimulus that augments NAD+ biosynthesis, modulates hypoxia-inducible factor-1α-dependent adaptive responses, fosters neurotrophic signaling, and enhances both vascular and metabolic health of the brain. Furthermore, emerging evidence suggests that the gut microbiota directly contributes to NAD+ homeostasis by regulating vitamin B3 precursor availability, tryptophan metabolism, and host metabolic signaling, while also influencing the efficacy of NAD+-enhancing interventions, thereby affecting systemic inflammation, metabolic equilibrium, and the production of neuroactive metabolites. Collectively, the interaction among vitamin B3 supplementation, physical activity, and gut microbiota may represent a promising framework for investigating strategies aimed at supporting cognitive health and brain resilience during aging, although definitive therapeutic applications require further validation. This review integrates current molecular, preclinical, and clinical evidence to establish mechanistic links between NAD+ metabolism, brain aging, cognitive dysfunction, and neurodegeneration, while emphasizing current limitations and future translational challenges associated with combining vitamin B3 metabolites, exercise, and microbiome-targeted approaches.
    Keywords:  NAD+ repletion; brain aging; exercise; gut microbiome dynamics; neurodegenerative disease; vitamin B3 metabolites
    DOI:  https://doi.org/10.3389/fnut.2026.1865556
  32. Front Immunol. 2026 ;17 1877232
    Antigen-experienced NK-T cells: integrating new insights and exploring therapeutic potential in cancer immunotherapy.
    Shunichiro Kuramitsu, Masasuke Ohno, Mitsugu Fujita.
      Conventional CD8+ T cells can acquire natural killer (NK) cell receptors upon persistent antigen exposure, forming antigen-experienced NK-T (AENK-T) cells. Their dual-state plasticity within the tumor immune microenvironment determines cancer immunotherapy outcomes. This narrative review synthesizes recent transcriptomic, epigenomic, and functional data to define the trajectory, regulation, and therapeutic relevance of AENK-T cells. The analysis establishes a "temporal hierarchy" differentiating AENK-T cells from innate-like T cells: activating NK receptors (NKG2C, NKG2D) emerge early, while inhibitory receptors (NKG2A, killer-cell immunoglobulin-like receptors, KLRB1) accumulate under sustained stimulation. Mechanistically, BCL11B downregulation and the T-bet-Zeb2 axis stabilize a cytotoxic Effector AENK-T state. Conversely, the TOX-LAG-3 loop and SOX4-ID3 axis drive transition into a suppressive Exhausted AENK-T state, mirroring terminal exhaustion. The tumor immune microenvironment accelerates this shift via hypoxia, metabolic competition, and TGF-β, contrasting with chronic infection models. Translating these findings, an evaluation of emerging strategies, such as NKG2A blockade, biomarker-guided patient selection, and next-generation chimeric antigen receptor (CAR)-T cell engineering, suggests that temporally informed approaches targeting the AENK-T trajectory may overcome current immune checkpoint therapy limitations.
    Keywords:  T cell exhaustion; antigen-experienced NK-T (AENK-T) cells; chimeric antigen receptor (CAR)-T cells; immune checkpoint blockade; innate-like T cells; natural killer cell receptors; tumor immune microenvironment (TIME)
    DOI:  https://doi.org/10.3389/fimmu.2026.1877232
  33. Liver Int. 2026 Nov;46(11): e70897
    Intrahepatic Tissue-Resident CD8+ T-Cell Programmes Associate With Fibrosis and Local Immune Remodelling in Autoimmune Hepatitis.
    Victoria Stary, Sarah Losek, Magdalena Mairinger, Gerhard Prager, Jonas Santol, Patrick P Starlinger, Thomas Reiberger, Albert F Stättermayer, Georg Stary.
       BACKGROUND AND AIMS: Autoimmune hepatitis is an immune-mediated liver disease characterized by chronic inflammation and progressive fibrosis. Tissue-resident memory T cells mediate organ-specific immunity, but their role in autoimmune hepatitis remains poorly understood. We characterized tissue-residency-associated T-cell populations and their cytokine profiles, assessed associations with disease severity and determined whether these signatures were reflected in peripheral blood.
    METHODS: Paired blood and liver samples were obtained from 19 patients with autoimmune hepatitis. Comparator cohorts included 20 patients with metabolic dysfunction-associated steatotic liver disease and 20 surgical patients providing non-inflamed adjacent non-tumorous liver tissue. Multiparameter flow cytometry assessed tissue-residency markers, T-cell differentiation and cytokine production after polyclonal stimulation. Immune phenotypes were correlated with histological and clinical parameters.
    RESULTS: Autoimmune hepatitis was associated with compartment-specific remodelling of T-cell differentiation states and intrahepatic enrichment of CD8+ T cells expressing CD69, CD103 and CXCR6 relative to paired blood and comparator liver tissues. Intrahepatic CD8+ T cells exhibited an interferon-γ-dominant cytokine profile, whereas CD4+ T cells showed broader interferon-γ-, interleukin-17A- and interleukin-4-associated responses. Despite the enrichment of tissue-residency-associated CD8+ T cells, cytokine-producing CD8+ T-cell populations with and without a tissue-resident memory phenotype contributed comparably to the hepatic T-cell compartment. Tissue-residency-associated phenotypes correlated positively with Ishak fibrosis stage, whereas the frequency of interferon-γ-positive intrahepatic CD8+ T cells correlated inversely with fibrosis.
    CONCLUSIONS: Autoimmune hepatitis was characterized by intrahepatic accumulation of phenotypically distinct and functionally active CD8+ tissue-resident memory T cells associated with fibrosis. This immune profile was not reflected in paired blood, indicating compartmentalized hepatic immune remodelling.
    Keywords:  CD8 T cells; autoimmune hepatitis; liver fibrosis; liver immunology; tissue residency; tissue‐resident memory T cells
    DOI:  https://doi.org/10.1111/liv.70897
  34. Nat Rev Immunol. 2026 Oct 09.
    LAG3 checkpoint function and its mechanism of action in therapeutic targeting.
    Yong Jiang, Dario A A Vignali, Haopeng Wang.
      Lymphocyte activation gene 3 (LAG3) protein is a key immune inhibitory checkpoint receptor that suppresses T cell activation, proliferation and effector functions to maintain immune homeostasis and tolerance. In persistent pathological settings, chronic T cell receptor (TCR) signalling, together with sustained LAG3 signalling and other inhibitory receptor signalling, drives T cell dysfunction, highlighting LAG3 as a promising therapeutic target. However, more than 30 years after its discovery, the fundamental mechanisms governing LAG3 signalling and function remain incompletely defined. Elucidating LAG3 downstream signalling pathways and the mechanisms of action of LAG3-blocking antibodies is essential for identifying optimal clinical indications, developing predictive biomarkers, designing more effective LAG3-targeted therapeutics and maximizing clinical efficacy. Recent advances have revealed key molecular mechanisms, including constitutive tonic signalling, ligand-induced ubiquitination-dependent signalling switches and LAG3-TCR proximity-mediated suppression. In this Review, we comprehensively examine LAG3 signalling mechanisms, synthesize current understanding of its functional effect on T cells, discuss emerging therapeutics and their mechanisms of action, and evaluate biomarker strategies for patient selection. We conclude by highlighting key challenges and outlining future directions for LAG3-targeted immunotherapy in oncology and autoimmune disease.
    DOI:  https://doi.org/10.1038/s41577-026-01359-2
  35. Cancer Res. 2026 Oct 05.
    Targeting SLC38A5 Overcomes αPD-1 Immunotherapy Resistance by Alleviating Glutamine Competition Between Glioblastoma Cells and T Cells.
    Zhuohao Liu, Jiani Lin, Tao Chen, Weimin Zhang, Ran Ye, Ying-Gui Yang, Na Li, Jiayi Zhou, Guisen Tan, Chenci Wang, Zhengwei Wang, Xiaoping Wu, Kenneth King-Yip Cheng, Jie Mao, Ming Gao, Jiacheng Liu, Xiaojuan Pei, Chi-Fai Ng, Yuliang Wang, Dinglan Wu.
      Despite the clinical success of programmed cell death protein 1 (PD-1) checkpoint blockade in many cancer types, its efficacy in glioblastoma remains notably limited, underscoring the critical need to uncover primary resistance mechanisms and identify synergistic therapeutic targets. To discover genes modulating αPD-1 immunotherapy response, we performed an in vivo CRISPR-Cas9 screen in immunocompetent mice bearing glioblastoma, which prioritized the glutamine (Gln) transporter SLC38A5 as a candidate modulator of αPD-1 immunotherapy efficacy. In human glioblastoma, SLC38A5 was significantly upregulated compared with normal brain tissue. Ablation of SLC38A5 did not impair glioblastoma cell intrinsic growth but profoundly sensitized glioblastoma to αPD-1 therapy in a CD8+ T cell-dependent manner, leading to enhanced anti-tumor immunity and tumor control. Mechanistically, SLC38A5 deficiency created a Gln-enriched tumor microenvironment by impairing Gln uptake of glioblastoma cells. This metabolic rewiring enhanced CD8+ T cell function via SLC1A5-dependent Gln utilization and promoted MHC-I-mediated antigen presentation in glioblastoma cells through a Gln-glutathione (GSH)-reactive oxygen species (ROS) axis. Furthermore, an SLC38A5-targeting nanobody was developed that efficiently accumulated in orthotopic glioblastoma and potentiated αPD-1 therapy to suppress brain tumor growth in vivo. Overall, this study establishes SLC38A5 as a metabolic immune regulator in glioblastoma and presents a promising Nb-based strategy for overcoming αPD-1 immunotherapy resistance.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-0774
  36. Nat Aging. 2026 Oct 05.
    Decline of chaperone-mediated autophagy in aging impairs macrophage clearance of senescent cells.
    Rebecca Sereda, Kristen Lindenau, Antonio Diaz, Zhaohui Liu, Olaya Santiago-Fernández, Rabia R Khawaja, Ronald Cutler, Jazmin Calyeca, Mericka McCabe, Sylvére Durand, Fanny Aprahamian, Natalia Del Pilar Vanegas, Hu Chen, Felipe Vilicich, Bhakti Chavda, Yair Botbol, Guido Kroemer, Toren Finkel, Evripidis Gavathiotis, Simone Sidoli, Ana L Mora, Mauricio Rojas, Susmita Kaushik, Ana Maria Cuervo.
      Autophagy dysfunction and senescence are established drivers of aging, but their potential interaction remains poorly understood. Here we show that age-related decline of chaperone-mediated autophagy (CMA), a pathway for selective lysosomal protein degradation, changes senescent cell properties and impairs their immune clearance. CMA-deficient cells undergo senescence but acquire proteomic, metabolic and secretory features resembling those in aged senescent cells. Their senescence-associated secretory phenotype exhibits enhanced pro-senescence effects on neighboring cells and inhibits macrophage CMA, which impairs their ability to engulf senescent cells. Accordingly, blockage of CMA specifically in macrophages increases senescent cell accumulation in mice and delays senescence resolution during wound healing. Conversely, pharmacological CMA activation reduces senescent cell burden in aged mice and disease severity in a pulmonary fibrosis mouse model. Our findings identify CMA decline as a driver of senescent cell persistence and highlight CMA upregulation as a promising strategy to promote senescence resolution in aged organisms.
    DOI:  https://doi.org/10.1038/s43587-026-01240-w
  37. bioRxiv. 2026 Aug 10. pii: 2026.08.08.743614. [Epub ahead of print]
    Cellular senescence is associated with age-related loss of liver zonation and hepatocyte function.
    Linshan Laux, Alisha Aristel, Syed Ali, Kathryn Lande, Meiyi Li, K Garrett Evensen, Aaron Havas, Zhen Miao, Jane Zhang, Samuel Peters, Jiayi Hu, Luise Angelini, Maggie Klaers, Jennie Brocksome, Adam Lewis, Nishitha Paidimukkala, Mary E Brown, Chase M Carver, Marissa J Schafer, Jeffrey H Albrecht, April Wehner, Peter Adams, Constantin Aliferis, Oyedele Adeyi, Sundeep Khosla, Xiao Dong, Jinhua Wang, Paul D Robbins, Nancy Zhang, Laura J Niedernhofer.
      The liver is organized into tightly regulated zones with distinct metabolic functions but zonation erodes with age. Cellular senescence contributes to aging and liver diseases, however, its impact on aging biology is ill-defined. As part of The Cellular Senescence Network Consortium, we used multiple spatial transcriptomics approaches (GeoMx, Visium, CosMx) with snRNA-seq to profile senescence signatures, zonation markers, and metabolic pathways in livers from wild-type (WT) mice of multiple ages. We observed a loss of canonical zone signatures in aged mouse livers characterized by "expansion" of midlobular (zone 2) marker gene expression, accompanied by diminished expression of zone 3 marker genes by middle-age (18 months), indicative of loss of cell identity. Multiple analytic approaches identified distinct age-, zone- and sex-specific senescence signatures, which were significantly associated with zonation markers changes. This was recapitulated in Ercc1 mutant models of accelerated senescence, supporting a causal role of senescent cells in liver aging. A "no-zone" hepatocyte-like cluster expanded with age and with the strongest Senescence-Associated Secretory Phenotype (SASP) profile. Gene expression profiles from senescent hepatocytes implicate decreased WNT signaling and increased BMP as contributing to age-related loss of zonation. Together, these data elucidate the role of senescent cells in driving aging biology in non-diseased liver through disruption of cell:cell signaling and the loss of metabolic and cell identity gene expression necessary for hepatocyte function.
    DOI:  https://doi.org/10.64898/2026.08.08.743614
  38. Cell Rep. 2026 Oct 07. pii: S2211-1247(26)01179-4. [Epub ahead of print]45(10): 118100
    A developmentally restricted γδ T cell-IL-17A axis supports mouse heart regeneration.
    Stephanie Vargas Aguilar, Matthieu Dos Santos, Wei Tan, Efrain Sanchez-Ortiz, Kenian Chen, Hui Li, Lin Xu, Ning Liu, Eric N Olson.
      Mammalian heart regeneration is restricted to a brief postnatal period during which neonatal-specific mechanisms, including a tightly regulated immune response, enable tissue repair. Here, we show that cardiac injury during the regenerative window induces the accumulation of a distinct γδ T cell population that is absent from older, non-regenerative hearts. Following injury, these cells serve as a rapid source of IL-17A, which shapes the timing and composition of the neonatal immune response. Genetic ablation of γδ T cells or disruption of IL-17 signaling limits heart regeneration and results in dysregulated immune cell infiltration and impaired cardiac function. Mechanistically, our data suggest that γδ T cell-derived IL-17A acts on myeloid cells to initiate a rapid, self-limited inflammatory response that facilitates apoptotic cell clearance and limits sustained inflammation. Our study identifies a developmentally restricted immune axis that supports heart regeneration and advances our understanding of how neonatal-specific immune circuits shape tissue repair.
    Keywords:  CP: developmental biology; CP: immunology; IL-17A; cardiac repair; cardio-immunology; development; heart regeneration; immunology; γδ T cells
    DOI:  https://doi.org/10.1016/j.celrep.2026.118100
  39. Cell Chem Biol. 2026 Oct 05. pii: S2451-9456(26)00331-4. [Epub ahead of print]
    Arginine methylation in immunoregulation: Mechanisms and therapeutic targeting.
    Song-Iee Han, Sachiko Toma-Fukai, Jun-Dal Kim, Koichiro Kako, Hiroaki Daitoku, Akiyoshi Fukamizu.
      Post-translational modifications (PTMs) are central regulators of immune cell function, linking extracellular signals to the regulation of intracellular gene expression. Among these, protein arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is a key mechanism that connects epigenetic control with signal transduction. PRMTs modify both histone and non-histone substrates, thereby regulating chromatin accessibility, transcriptional programs, and immune signaling pathways. Recent studies have shown that arginine methylation modulates immune cell activation, differentiation, and effector functions, whereas its dysregulation contributes to tumor immune evasion and chronic inflammation. Notably, alterations in PRMT activity have been increasingly suggested in age-associated immune remodeling and inflammaging. In this review, we integrate current evidence showing how PRMT-mediated arginine methylation coordinates chromatin regulation, RNA metabolism, and immune signaling, and examine how these mechanisms shape immune homeostasis, tumor immunity, inflammaging, and opportunities for therapeutic intervention.
    Keywords:  PRMTs; PTMs; arginine methylation; epigenetics; epigenomic remodeling; immunoregulation; inflammaging; post-translational modifications;; protein arginine methyltransferases;
    DOI:  https://doi.org/10.1016/j.chembiol.2026.09.003
  40. Front Immunol. 2026 ;17 1908222
    Mitochondrial dysfunction as a metabolic checkpoint of immunotherapy response in colorectal cancer.
    Lorenzo Tomassini, Marco Colella, Giovanni Monteleone, Carmine Stolfi, Federica Laudisi.
      Immunotherapy has markedly improved outcomes across multiple cancer types; however, colorectal cancer (CRC) remains largely refractory, with meaningful responses mostly restricted to tumors harboring deficient mismatch repair and high microsatellite instability (dMMR/MSI-H), which represent only a small fraction of CRC cases. Emerging evidence suggests that mitochondrial dysfunction may be viewed as a metabolic checkpoint, representing a conceptual framework through which mitochondrial-dependent processes regulate antitumor immunity and immunotherapy response in CRC. In tumor cells, mitochondrial reprogramming enhances reliance on oxidative phosphorylation, promotes hypoxia, and drives metabolite accumulation, collectively shaping an immunosuppressive tumor microenvironment. In parallel, tumor-infiltrating T-cells exhibit mitochondrial dysfunction characterized by impaired biogenesis, reduced respiratory capacity and features of exhaustion, thereby limiting the efficacy of immune checkpoint inhibitors (ICIs). In this review, we summarize current insights into the role of mitochondrial pathways in regulating tumor immune escape and T-cell dysfunction in CRC. We further discuss emerging therapeutic strategies aimed at targeting metabolic vulnerabilities to overcome resistance and potentially enhance responses to immunotherapy.
    Keywords:  T-cell exhaustion; cancer immunotherapy; colorectal cancer; immune checkpoint inhibitors; immune evasion; metabolic reprogramming; mitochondrial dysfunction; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1908222
  41. 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
  42. Blood. 2026 Oct 08. pii: blood.2026034296. [Epub ahead of print]
    KPNA2-Mediated MYC Nuclear Import Enhances CAR-T Cell Memory and Potentiates Antitumor Efficacy.
    Shi Han, Delin Kong, Chen Yang, Fang Ye, Juan Yue, Kexin Wang, Haiqiong Zheng, Zhuomao Mo, Xinghua Liang, Kejia Hu, Jianyu Wang, Penglei Jiang, Xia Li, Meng Zhang, Xiangjun Zeng, Yijin Chen, Lin Yang, Yanyan Wang, Mi Shao, Pengxu Qian, Yongxian Hu, He Huang, Dongrui Wang.
      Chimeric antigen receptor (CAR)-T cell therapy demonstrates remarkable clinical efficacy, yet limited persistence and functional exhaustion impede durable responses. While memory-like phenotypes are associated with sustained CAR-T function and improved clinical outcomes, the underlying molecular mechanisms of CAR-T cell memory maintenance remain incompletely defined and we still lack actionable strategy to sufficiently promote CAR-T cell memory formation. Here, we identified that Karyopherin Subunit Alpha 2 (KPNA2)-mediated MYC nuclear import robustly enhanced CAR-T cell memory and antitumor function. In clinical CAR-T cell products, KPNA2 expression and MYC pathway activation are correlated with superior therapeutic potency. Overexpressing MYC showed negligible effect on CAR-T cell function due to insufficient nuclear import; in contrast, incorporating KPNA2 in CAR-T cells facilitated MYC nuclear import, augmented memory formation, enhanced cytotoxicity and antitumor activity both in vitro and in vivo. Such functional improvement was not associated with risks of transformation in KPNA2-overexpressing CAR-T cells. Mechanistically, our integrated transcriptomic and epigenomic analyses revealed that KPNA2 increased MYC occupancy at memory-associated gene loci, upregulating T cell memory programs. Furthermore, virtual drug screening identified the small molecule TMS which potentiates KPNA2-MYC interaction. TMS treatment of CAR-T cells enhanced MYC nuclear accumulation, promoted memory-oriented transcriptional profiles, and improved antitumor potency in preclinical models. These findings established KPNA2-MYC interaction as a pivotal mechanism governing CAR-T cell memory formation, providing genetic and pharmacological strategies to advance therapeutic T cell design and manufacturing.
    DOI:  https://doi.org/10.1182/blood.2026034296
  43. Exp Mol Med. 2026 Oct 09.
    Microbial cues and T cell immunity: deciphering their interactions in chronic liver disease.
    Yinuo Liu, Baichao Yu, Qiaoyan Liu, Xiong Ma, Ruqi Tang.
      Chronic liver disease (CLD) poses a major global health challenge, as its progression to cirrhosis and hepatocellular carcinoma significantly contributes to worldwide morbidity and mortality. Mounting evidence has identified the gut microbiota as a critical modulator of CLD progression, primarily via the gut-liver axis. The liver is continuously exposed to gut-derived signals through the portal circulation, while reciprocally secreting bioactive mediators that shape intestinal microbial composition and function. This bidirectional network enables intricate crosstalk between the gut microbiota and the host immune system. In particular, T lymphocytes, the central effectors of adaptive immunity, are tightly regulated by gut microbiota and their metabolites. Conversely, T cells also modulate the gut microbial ecosystem. Herein, we summarize current knowledge on this bidirectional crosstalk, focusing on how gut microbiota shape T cell differentiation, function and plasticity, as well as the reciprocal impact of T cells on the gut microbiota. Furthermore, we evaluate how these interactions influence the development and progression of various CLDs, including autoimmune liver diseases, alcohol-associated liver disease, metabolic dysfunction-associated steatotic liver disease and viral hepatitis. Finally, we discuss the therapeutic potential of targeting gut microbiota-T cell interactions through immunomodulatory and microbiota-directed strategies to offer novel therapeutic approaches.
    DOI:  https://doi.org/10.1038/s12276-026-01831-y
  44. Aging Cell. 2026 Oct;25(10): e70703
    Inhibiting Glutaminase Reverses Senescence-Associated Mitochondrial Dysfunction and Skeletal Muscle Decline.
    Hamsa Vardini Senthil Kumar, Debanik Choudhury, Pedro Lei, Pihu Mehrotra, Shahryar Shahini, Sydney Swedick, John Toftegaard, Stelios T Andreadis.
      Age-associated loss of skeletal muscle mass and function, also known as sarcopenia, is closely linked to mitochondrial dysfunction. In this study, we report that senescent skeletal muscle myoblasts exhibit elevated activity and expression of the enzyme glutaminase (GLS1), which is mediated by p38 MAPK signaling and leads to intracellular urea accumulation that impairs mitochondrial function. Pharmacological inhibition of GLS1 with CB-839 reduced urea levels, restored the expression of electron transport chain (ETC) complexes, and improved mitochondrial function. Consistent with our in vitro findings, CB-839 administration to progeroid mice similarly upregulated ETC complexes and enhanced mitochondrial respiratory capacity in skeletal muscle, leading to improved structural integrity and enhanced muscle strength. Together, these findings suggest that targeting glutamine metabolism via GLS1 inhibition may represent a promising therapeutic strategy to ameliorate age-related skeletal muscle decline by restoring mitochondrial health.
    DOI:  https://doi.org/10.1111/acel.70703
  45. Nat Med. 2026 Oct 08.
    Author Correction: Natural killer T cells and CD8+ T cells are dispensable for T cell-dependent allergic airway inflammation.
    Jyoti Das, Paul Eynott, Ray Jupp, Alfred Bothwell, Luc Van Kaer, Yufang Shi, Gobardhan Das.
      
    DOI:  https://doi.org/10.1038/s41591-026-04709-8
  46. EMBO Mol Med. 2026 Oct 06.
    Inhibition of CDK12/CDK13-CYCLIN K rewires P-TEFb signaling to reverse HIV-1 latency and modulate cellular gene expression.
    Praveenkumar Murugavelu, Jagrity Rani, Heli Glebko, Ina Ambiel, Nadine Tibroni, Nili Tickotsky, Ferdinand Heyn, Philipp Schommers, Liron Levin, Alona Kuzmina, Oliver Till Fackler, Ran Taube.
      Persistent HIV-1 latency in long-lived CD4⁺ T-cell reservoirs remains a major obstacle towards viral eradication. Current antiretroviral therapy (cART) exhibits limited clinical efficacy, highlighting the need for new therapeutic interventions. Here, we identify the CDK12/CDK13-Cyclin K (CCNK) complex as a regulator of HIV-1 latency. Pharmacological inhibition of CDK12/CDK13-CCNK with the SR-4835 inhibitor robustly reversed HIV-1 latency in the absence of additional stimuli, both in T cell models and in primary CD4⁺ T cells from people living with HIV-1 receiving cART. Targeting of CDK12/CDK13-CCNK with SR-4835 further synergized HIV-1 latency reversal and enhanced viral reactivation when co-treated with established Latency Reversal Agents. Mechanistically, CDK12/CDK13-CCNK inhibition promoted the release of P-TEFb (CDK9/CYCLIN T) from its inhibitory 7SK snRNP complex, resulting in increased recruitment of RNA polymerase II, CDK9 activation, and remodeled chromatin that overall drove productive HIV-1 transcription. Beyond HIV-1 reactivation, our findings reveal a previously unrecognized compensatory interplay between transcriptional kinases that activate gene expression, thereby rewiring cellular transcriptional programs. Together, this study identifies CDK12/CDK13-CCNK complex as a therapeutic target for HIV-1 latency reversal and provides a mechanistic rationale for improving strategies aimed at achieving an HIV cure.
    DOI:  https://doi.org/10.1038/s44321-026-00536-z
  47. Crit Rev Oncol Hematol. 2026 Oct 07. pii: S1040-8428(26)00525-1. [Epub ahead of print]228 105638
    Reprogramming the myeloid-T cell ecosystem through engineered oncolytic viruses for durable antitumor immunity.
    Chuanjian Wu, Wanglu Gu, Andong Qin, Hanzhang Liu, Wen Zheng, Xingyan Pan, Yifan Zhang, Bingyu Shen, Rong Sun, Dong Shen, Yihui Fan.
      Oncolytic virotherapy (OVT) has emerged as a promising immunotherapeutic strategy that combines selective tumor destruction with systemic immune activation. However, durable clinical responses remain limited because current approaches largely focus on viral replication and oncolysis while overlooking the immune networks that govern long-term tumor control. Emerging evidence indicates that therapeutic efficacy is determined by the dynamic interplay between myeloid and T-cell populations, which collectively regulate antigen presentation, T-cell priming, effector function and immune suppression. In this Review, we propose the myeloid-T cell ecosystem as a conceptual framework for understanding and optimizing OVT. We discuss how engineered oncolytic viruses function as programmable immune modulators that simultaneously enhance antigen presentation, reprogram immunosuppressive myeloid cells, relieve MDSC-mediated inhibition and reinforce productive crosstalk with effector T cells. We further highlight viral engineering strategies and rational combination therapies that coordinately engage innate and adaptive immunity to reshape the tumor immune microenvironment. Finally, we discuss key challenges, including tumor heterogeneity, the balance between antiviral and antitumor immunity, viral delivery and biosafety. We argue that the future of OVT lies in precisely engineering the myeloid-T cell ecosystem to convert transient antiviral inflammation into durable, self-sustaining antitumor immunity, providing a conceptual roadmap for next-generation precision viro-immunotherapy.
    Keywords:  Combination therapy; Oncolytic virotherapy，Myeloid–T cell ecosystem，Tumor heterogeneity
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105638
  48. Mol Ther Nucleic Acids. 2026 Dec 08. 37(4): 103081
    Human T cell engineering via serial delivery of mRNA encapsulated within lipid nanoparticles.
    Apoorva Ramamurthy, Giulia Scimonelli, William L Murphy, Krishanu Saha.
      Human T cells modified with nucleic acids constitute a powerful and emerging therapeutic modality for cancer, autoimmune disorders, and aging-related diseases. However, delivering nucleic acids, such as mRNA encoding synthetic receptors, transcription factors, cytokines, or genome editors to T cells can be challenging, as nucleic acids can unintentionally reduce viable T cell yield and function, particularly when delivered sequentially ex vivo. To address this challenge, we evaluated the efficiency of serial non-viral delivery of synthetic mRNA encapsulated within lipid nanoparticles (LNPs) incorporating cationic lipid, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and fusogenic helper lipid, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). DOTAP/DOPE-containing LNPs delivered mRNA more efficiently than a clinically benchmarked 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)-containing LNP formulation, resulting in significantly higher protein expression in primary human T cells. Furthermore, DOTAP/DOPE-LNP delivery resulted in 100% higher yield of live cells compared to electroporation, an advantage that compounded over serial rounds, with LNP-treated cultures maintaining substantially more viable cells through all four transfections. Additionally, serial transfection of mRNAs encoding a therapeutically relevant chimeric antigen receptor (CAR) payload produced functional CAR T cells. These results demonstrate that LNPs can be a viable platform for serial and iterative T cell engineering using multiple mRNA payloads, providing an alternative to electroporation for the engineering of therapeutic T cells.
    Keywords:  CAR T cell engineering; DOPE; DOTAP; LNP; MT: Delivery Strategies; T cells; cell therapy manufacturing; electroporation; mRNA delivery; non viral gene delivery
    DOI:  https://doi.org/10.1016/j.omtn.2026.103081
  49. Aging Cell. 2026 Oct;25(10): e70759
    Chronic Senolytic Treatment and/or Aerobic Exercise Reduce Senescence and Improve Myocardial Function During Aging in the Heart.
    Ryan T Bevington, Amanda L Johnson, Briana L Hockey, Val A Fajardo, Gianni Parise.
      Aging is the predominant risk factor for cardiac dysfunction, driven primarily through a decline in cardiomyocyte and overall myocardial performance. Cellular senescence is becoming increasingly linked to its development, as senescent cardiomyocytes and interstitial cells accumulate with age and exhibit persistent DNA damage, mitochondrial dysfunction, and inflammation that collectively impair ventricular relaxation and contractility. Senolytics, which selectively eliminate senescent cells, effectively clear cardiac senescence and its burden, while aerobic exercise has shown promise as a non-pharmacological intervention capable of modulating senescence. Despite this, neither approach has been evaluated as a long-term preventive strategy or whether combining exercise with senolytics produces an additive effect. We hypothesized that when combined, chronic senolytics and aerobic exercise would produce a synergistic clearance of senescent myocardial cells leading to improved cardiac function. Male and female C57BL/6N mice (12-months-old) were randomly allocated to each group and received their intervention for 9-months: naturally aged (VEH, n = 12), aerobic exercise (EX, n = 11), senolytics Dasatinib + Quercetin (D + Q) (SEN, n = 15) or both combined (SENEX, n = 16). Chronic D + Q, exercise, or both, significantly lowered the proportion of p16+, p21+, and γ-H2AX+ cardiomyocytes and interstitial cells, while improving myocardial performance and diastolic function compared to naturally aged mice. At the whole-heart level, protein expression of p16 and p21 increased with age, but was not altered alongside SASP by any intervention. Collectively, these findings demonstrate that long-term exercise or senolytics limit senescence at the cellular level within the myocardium, and improve ventricular function, positioning exercise or senolytics as promising strategies to mitigate age-related cardiac dysfunction.
    Keywords:  aging; exercise; heart; myocardium; senescence; senolytics
    DOI:  https://doi.org/10.1111/acel.70759
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