bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2026–08–09
twenty-two papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Translational repression of 5' TOP mRNAs in chronically activated CD8+ T cells in vitro.
  2. Non-redundant functions of NFATc1 in survival and NFATc2 in generation of exhausted CD8+ T cells.
  3. T cell-based immunotherapy in solid tumors: mechanistic barriers and emerging opportunities.
  4. Enforcing mTORC1 activity in therapeutic CD4+ T cells promotes persistence but eventual immune exhaustion.
  5. T cell-nanodrug conjugates synchronize vascular normalization and immune activation for solid tumor therapy.
  6. Integrating T cell signaling and metabolism to enhance T cell engager responses in solid tumors.
  7. HPV-driven metabolic reprogramming promotes T cell exhaustion: targeting immunometabolic barriers with natural products.
  8. Metabolic Profiling of Circulating and Tumour-Infiltrating T Cells Uncovers Bioenergetic Checkpoints Linked With Immune and Clinical Skewing in Melanoma Patients.
  9. Glucose metabolism in tumor-associated macrophage plasticity and cancer immunity.
  10. Metabolic-epigenetic crosstalk in innate immune cell plasticity within the tumor microenvironment.
  11. Selenium-Binding Protein 1 Deficiency Inhibits the Antitumor Immunity of Dendritic Cells.
  12. Tumoral AMER1 driven dopamine synthesis triggers cancer cell pyroptosis and licenses CD8+ T cell immunity in colorectal cancer.
  13. Metabolic exhaustion and immune ageing in rheumatoid arthritis.
  14. Targeting T-cell exhaustion and tumour immune evasion: a review of emerging strategies.
  15. Metabolic rewiring of the dendritic cell-T cell axis: tumour-derived barriers and therapeutic opportunities.
  16. Loss of SETD2-mediated H3K36me3 Drives CD8+ T Cell Exhaustion in Lung Cancer through CXCL-dependent PMN-MDSC Recruitment and Arginine Deprivation.
  17. Inhibitory TIGIT signaling is dependent on T cell receptor activation.
  18. METTL7A Downregulation Drives SLC1A5-Mediated Glutamine Competition to Promote Tumor Proliferation and Suppress CD8+ T Cell Immunity in Gastric Cancer.
  19. Post-translational modifications in metabolic reprogramming: implications for metabolic therapy and immunotherapy in cancer.
  20. Intranodal injection of PD1 antibody enhances memory T cell responses to improve the efficacy of neoantigen vaccines.
  21. Correction: NOSIP overexpression promotes long-term persistence of CD8+ T cells during chronic infection.
  22. PKM2 works "off the books" to drive effector T cell function in MS.
  1. RNA Biol. 2026 Aug 06.
    Translational repression of 5' TOP mRNAs in chronically activated CD8+ T cells in vitro.
    Erica S Pledger, Navya Ambavaram, Lucas Ferguson, Jamie H D Cate.
      T cell exhaustion is a dysfunctional state that arises during chronic infections and cancer, characterized by impaired effector functions and sustained expression of inhibitory receptors. While transcriptional, epigenetic, and metabolic rewiring have been well documented in exhausted T cells, a comprehensive understanding of how translation is regulated in this state remains incomplete. To address this gap, we performed ribosome profiling and RNA sequencing on in vitro chronically activated human CD8+ T cells to globally assess translational control during a model of T cell exhaustion. Our analyses reveal a marked repression of 5' terminal oligopyrimidine (TOP) mRNAs during chronic activation. Unexpectedly, we demonstrate that this translational repression occurs despite evidence of elevated mTOR activity. These findings uncover a previously unknown layer of translational control in exhausted T cells.
    Keywords:  T cell; TOP mRNAs; chronic activation; exhaustion; mTOR; ribosome profiling; translation regulation
    DOI:  https://doi.org/10.1080/15476286.2026.2715355
  2. Front Immunol. 2026 ;17 1869029
    Non-redundant functions of NFATc1 in survival and NFATc2 in generation of exhausted CD8+ T cells.
    Salvador Sampere-Birlanga, Stefan Klein-Hessling, Miriam Campillo Prados, Anfei Huang, Hao Wu, Andreas Rosenwald, Wolfgang Kastenmüller, Edgar Serfling, Martin Vaeth, Friederike Berberich-Siebelt.
      Persistent antigenic stimulation leads to the dysfunction of CD8+ cytotoxic T cells. These "exhausted" TEX cells exhibit reduced proliferative capacity, impaired effector function, and increased expression of co-inhibitory receptors. Chronic antigen receptor stimulation induces the expression of NFATc1/αA, a short isoform of NFATc1 that promotes TEX cell survival. The induction of NFATc1/αA is accompanied by a significant decrease in NFATc2 expression. NFATc2 limits the expression of stemness-associated genes, such as Tcf7, Sell, and Id3. It also supports the expression of Prf1, Gzmb, and the TEX marker gene Havcr2. Therefore, ablation of NFATc2 mitigates functional exhaustion of CD8+ T cells during chronic viral infection and antitumor immunity. Our findings illustrate that NFATc1 promotes the survival of TEX cells, while NFATc2 promotes the terminal differentiation and dysfunction of exhausted CD8+ T cells. The data suggest a non-redundant interplay between NFATc1 and NFATc2, each playing a distinct role in controlling CD8+ T-cell exhaustion. These findings open novel avenues to enhance the efficacy of immune checkpoint and CAR T-cell therapies.
    Keywords:  CD8+ T cells; NFATc2; Nfatc1; T-cell exhaustion; T-cell survival
    DOI:  https://doi.org/10.3389/fimmu.2026.1869029
  3. BMB Rep. 2026 Aug 03. pii: 6874. [Epub ahead of print]
    T cell-based immunotherapy in solid tumors: mechanistic barriers and emerging opportunities.
    Hojin Chun, Hyunjin Ju, Sung-Min Hwang.
      T cell-based immunotherapies have transformed the treatment of hematological malignancies, but their efficacy in solid tumors remains inconsistent. Unlike blood cancers, solid tumors present multiple barriers that impede T cell infiltration, metabolic fitness, antigen recognition, and long-term persistence. These barriers include structural exclusion by the stroma, tumor-driven metabolic competition, antigen plasticity, and the progressive epigenetic fixation of T cell exhaustion states. This review integrates our current understanding of T celldirected therapeutic approaches and examines the tumorintrinsic and microenvironmental mechanisms that limit their activity in solid malignancies. We discuss how chronic stress signaling, altered nutrient availability, glycan-mediated epitope masking, and transcriptional reprogramming collectively destabilize therapeutic T cell function. Finally, we evaluate emerging strategies designed to remodel the tumor niche, diversify antigen targeting, and enhance T cell metabolic and epigenetic resilience. Thus, developing a mechanistic framework that combines intrinsic T cell reprogramming with adaptation to the tumor context will be crucial for extending durable T cell-mediated immunity to solid cancers.
  4. J Immunol. 2026 Aug 04. pii: vkag206. [Epub ahead of print]215(8):
    Enforcing mTORC1 activity in therapeutic CD4+ T cells promotes persistence but eventual immune exhaustion.
    Francesca Sillito, Elisa Armbrecht, Aideen T O'Neill, Andrew McIntyre, Melville Nyatondo, Angelika Holler, Lauren A Callender, Sian M Henson, Hans Stauss, Ronjon Chakraverty.
      There is substantial interest in developing novel engineering strategies to promote the sustained metabolic fitness of therapeutic T cells. We previously showed that overexpression of RAS homologue enriched in brain (RHEB), a positive regulator of mammalian target of rapamycin complex 1 (mTORC1), promotes aerobic glycolysis and increases the anti-tumor functions of effector CD8+ T cells. To address whether these effects are conserved in CD4+ T cells, we have now examined how enforced activation of mTORC1 activity affects CD4+ T cell differentiation and function. Rheb overexpression induced a more balanced metabolic shift in CD4+ T cells than in CD8+ T cells, with increases in both oxidative phosphorylation and aerobic glycolysis. Although Rheb overexpression initially increased CD4+ T cell activation and proliferation in vitro, the underlying population architecture was complex, involving a shift to both more proliferative, cytotoxic-like cell states as well as more quiescent cell clusters characterised by counter-regulation of mTORC1 activity. Following adoptive transfer, tumor antigen-specific Rheb-transduced CD4+ T cells showed greater persistence but were less efficient than controls in eliminating tumor. This functional deficiency could be explained by a greater propensity of persisting Rheb-transduced CD4+ T cells to develop features of immune exhaustion, as evidenced by expression of multiple co-inhibitory receptors and impaired proliferation upon tumor rechallenge. Together, these data demonstrate the dynamic population response to tuning of T cell mTORC1 and the need to separately appraise cellular outputs of therapeutic CD4+ versus CD8+ T cells when metabolic pathways are manipulated by the same method.
    Keywords:  CD4+ T cell; exhaustion; immunotherapy; mTORC1
    DOI:  https://doi.org/10.1093/jimmun/vkag206
  5. Sci Adv. 2026 Aug 07. 12(32): eadp2955
    T cell-nanodrug conjugates synchronize vascular normalization and immune activation for solid tumor therapy.
    Xin Yang, Ye Su, Xiaoyun Ye, Changjiang Liu, Xin Zhao, Yuyan Su, Qingyu Dong, Wenxuan Zeng, Xinghua Sui, Xiuman Zhou, Guanyu Chen, Yujia Zhang, Dalin Wu, Juan Liu.
      Adoptive T cell therapy requires T cells to infiltrate vascular tissues and preserve immune function. In solid tumor treatment, however, the surrounding microenvironment produces abnormal vasculature that impedes T cell infiltration. An approach that enables vascular normalization and enhances adoptive T cell function in parallel is essential for effective therapy but has not been reported. Here, we report the use of lenvatinib (LEN) to induce transient vascular normalization, thereby facilitating T cell infiltration. Moreover, LEN enhances T cell persistence by promoting the differentiation of T cells toward a memory phenotype. Our results indicate that the differentiation is by suppressing the PI3K-AKT-mTOR pathway, which drives effector differentiation, and by activating FOXO1, a transcription factor that promotes memory formation. To coordinate the transient vascular normalization and T cell enhancement, we link LEN-loaded, PD-L1-blocking micelles to T cells through acid-labile click chemistry, forming pH-responsive T cell-nanodrug conjugates. The conjugates synchronize the intratumoral release of LEN and the PD-L1 antagonist peptide OPBP-1, thereby coordinating vascular normalization, T cell differentiation, and checkpoint blockade. In vivo, the conjugates increased intratumoral CD8+ T cells and splenic memory T cells by over sixfold in B16-OVA tumors and achieved complete regression in a subset of MC38-OVA tumors without systemic toxicity, providing a promising strategy for solid tumor immunotherapy.
    DOI:  https://doi.org/10.1126/sciadv.adp2955
  6. Front Immunol. 2026 ;17 1887842
    Integrating T cell signaling and metabolism to enhance T cell engager responses in solid tumors.
    Michael Scaglione, Minal Engavale, Matthew G Chun, Deepali V Sawant, Daniel R Lu, Edward LaGory.
      T cell engagers (TCEs) have delivered meaningful clinical benefit to patients, with eight molecules currently FDA-approved for hematologic malignancies and two approved for solid tumor indications. Despite their transformative potential, successful TCE development across solid tumor indications remains challenging, and additional strategies are needed to maintain T cell fitness and function within the tumor microenvironment (TME). Next-generation TCE designs aim to increase response rate and bolster durability by optimizing or delivering additional signals to T cells. In recent years, cellular metabolism has emerged as a potent regulator of T cell function and fate, shaping immunity by supporting the biochemical requirements of immunological effector functions and acting as a direct immunoregulatory signal from the TME itself. Despite this, neither cell-intrinsic nor environmental roles for metabolism in regulating TCE responses in solid tumors have been explicitly explored. We propose that metabolism is a powerful lens for understanding TCE efficacy and resistance in solid tumors, integrating signals from both surface receptors and the biochemical environment of the TME to shape T cell function and therapeutic response. In this mini-review, we highlight how three classical T cell signaling axes - 1) the T cell receptor complex, 2) costimulatory receptors, and 3) cytokine receptors - drive metabolic rewiring to license immune function and shape T cell fate. We also explore how environmental cues such as nutrients or metabolic stressors govern T cell responses, highlighting how biochemical perturbations within the TME could hamper TCE efficacy. Finally, we highlight emerging methods for dissecting metabolic contributions to TCE responses, proposing that understanding the interplay between immunological signaling, cellular metabolism, and immune programming could inform the design of next-generation TCEs for solid tumors.
    Keywords:  T cell engagers (TCEs); immunotherapy; metabolism; signaling; solid tumors; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fimmu.2026.1887842
  7. Front Immunol. 2026 ;17 1892919
    HPV-driven metabolic reprogramming promotes T cell exhaustion: targeting immunometabolic barriers with natural products.
    Liang Wei, Hou Menghui, Zhang Dandan, Wang Xin, Chu Xinying, Ma Guangyi, Ma Jing.
       Background: High-risk human papillomavirus (HR-HPV) infection is the primary driver of cervical cancer. Emerging evidence indicates that the tumor microenvironment (TME) undergoes severe metabolic rewiring, which may accelerate T cell exhaustion (TEX) and impair immune checkpoint blockade (ICB). However, the molecular mechanisms coupling HPV-driven metabolism to T cell dysfunction remain incompletely elucidated.
    Methods: This review summarizes immunometabolic interactions in the cervical cancer TME. We examined the metabolic alterations induced by HPV oncoproteins (E6/E7) and how they reshape nutrient availability, lactate accumulation, and lipid peroxidation to drive anti-tumor CD8+ T cell exhaustion.
    Results: HPV-driven aerobic glycolysis and IDO1-mediated tryptophan catabolism establish severe metabolic barriers, causing nutrient deprivation and histone lactylation in infiltrating lymphocytes. These alterations are associated with persistent mitochondrial stress and ferroptosis, accelerating terminal TEX. In preclinical models, natural products (e.g., curcumin, berberine, quercetin, and artemisinin derivatives) can counteract this immunosuppressive rewiring by targeting checkpoints such as HIF-1α, PKM2, and AMPK; however, direct evidence of CD8+ tumor-infiltrating lymphocyte rescue in HPV-specific immune-competent systems remains limited, largely inferred from other tumor types. Nanomedicine delivery may further enhance the bioavailability and targeting of these herbal components.
    Conclusion: HPV-induced metabolic reprogramming is proposed to act as a fundamental checkpoint driving T cell exhaustion in cervical cancer. Targeting these immunometabolic barriers using natural compounds, particularly via nanomedicine-based delivery strategies, represents a promising but still largely preclinical avenue to synergize with conventional immunotherapies and potentially overcome resistance.
    Keywords:  T cell exhaustion; cervical cancer; human papillomavirus; metabolic reprogramming; natural products; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1892919
  8. Immunology. 2026 Aug 04.
    Metabolic Profiling of Circulating and Tumour-Infiltrating T Cells Uncovers Bioenergetic Checkpoints Linked With Immune and Clinical Skewing in Melanoma Patients.
    Hugo Brouque, Kareem Mahdy, Stephane Mouret, Sylvain Henry, Camille Niveau, Mélanie Cettour-Cave, Martin Pelosse, Florence de Fraipont, Julie Charles, Andrei Turtoi, Philippe Saas, Caroline Aspord.
      Metabolism is critical for immune cell functions. Tumours shape their microenvironment to render it metabolically hostile for infiltrating immune cells. While targeting immunometabolism emerges as a promising way to reinvigorate anticancer immunity, a deeper understanding of the metabolic disturbances of immune cells is needed. Here, we explored how the metabolic status of T cells governs immune skewing from circulating and tumour-infiltrating CD4+ and CD8+ T cells of melanoma patients at a single-cell level using the SCENITH method and targeted metabolomics. Circulating and tumour-infiltrating T cells from patients displayed a decreased mitochondrial dependency associated with an enhanced glycolytic capacity and a skewed metabolic reprogramming upon stimulation. Such metabolic disturbances were linked to the activation status, immune checkpoint profile and functional orientation of T cells, underlining critical connections between T-cell features and metabolic patterns. Targeted metabolomics within sorted CD4+/CD8+ T cells identified a decrease in citrulline, cysteine and threonine within all subsets in patients, together with a sharp rise in sterol cholesterol CE(20:2) and ceramide dhCer(d18:0/22:0) within tumour-infiltrating CD4+ T cells, and in glycerolipid DG(16:0/16:0) within CD8+ T cells in blood and tumour. We further outlined a metabolic-checkpoint-based signature composed of six genes coding enzymes/transporters connected to the imbalanced metabolites found within tumour-infiltrating T cells (LIPA, DGKA, GLUL, SLC38A1, SLC7A7, GCH1) that shape patients' clinical outcome. These findings outline the skewed bioenergetic profiles of T cells and depict metabolic checkpoints associated with immune subversion. Harnessing metabolic pathways is promising for developing innovative therapies to restore optimal anti-tumour responses and improve clinical success.
    Keywords:  SCENITH; T cells; immunometabolism; melanoma; metabolomics
    DOI:  https://doi.org/10.1111/imm.70185
  9. Front Cell Dev Biol. 2026 ;14 1885974
    Glucose metabolism in tumor-associated macrophage plasticity and cancer immunity.
    Bang Liu, Jin Wang, Xiulin Jiang, Xiangyu Chen.
      Tumor-associated macrophages (TAMs) are key immune cells in the tumor microenvironment and play critical roles in tumor progression, immune escape, and therapeutic response. Their functional plasticity is closely regulated by metabolic reprogramming, particularly glucose metabolism. Glucose-related pathways, including glycolysis, gluconeogenesis, the pentose phosphate pathway, glycogen metabolism, and pyruvate/lactate metabolism, influence TAM polarization, cytokine production, phagocytosis, antigen presentation, and T cell interactions. In many tumors, enhanced glycolysis and lactate accumulation promote M2-like TAM polarization and suppress CD8+ T cell activity, whereas certain metabolic programs may support M1-like anti-tumor functions under specific conditions. This mini review summarizes major glucose metabolic pathways involved in TAM regulation, highlights their context-dependent pro- and anti-tumor roles, and discusses therapeutic strategies for reprogramming TAM metabolism to improve anti-tumor immunity and immunotherapy response.
    Keywords:  HIF-1α; glucose metabolism; glycolysis; immunometabolism; lactate; metabolic reprogramming; pentose phosphate pathway (PPP); pyruvate metabolism
    DOI:  https://doi.org/10.3389/fcell.2026.1885974
  10. Exp Mol Med. 2026 Aug 06.
    Metabolic-epigenetic crosstalk in innate immune cell plasticity within the tumor microenvironment.
    Junho Noh, Jaehyun Lee, Chaelin You, Kyuho Kang.
      The tumor microenvironment exerts profound metabolic and epigenetic pressures that shape the plasticity of innate immune cells, influencing their capacity to promote or suppress tumor progression. Emerging evidence highlights the intricate interplay between metabolic reprogramming and epigenetic modifications in macrophages, neutrophils, and other innate immune populations within the tumor microenvironment. Tumor-derived metabolites, hypoxia, and nutrient availability dynamically regulate chromatin accessibility, histone modifications, and DNA methylation patterns, thereby driving context-dependent immune phenotypes. Notably, metabolic rewiring can imprint long-lasting epigenetic changes, a phenomenon known as innate immune memory, which alters subsequent immune responses. Here, we discuss how key metabolic pathways, including glycolysis, fatty acid oxidation, and amino acid metabolism, govern innate immune cell fate and function via epigenetic mechanisms. We also highlight recent advances in epigenomic profiling that have unveiled distinct chromatin landscapes associated with innate immune dysfunction across cancer types. Finally, we explore emerging therapeutic strategies that target the metabolic-epigenetic axis to restore innate immune surveillance and enhance immunotherapy efficacy. A deeper understanding of this metabolic-epigenetic crosstalk could reveal novel avenues for modulating innate immunity in cancer therapy.
    DOI:  https://doi.org/10.1038/s12276-026-01802-3
  11. Antioxid Redox Signal. 2026 Aug 05. 15230864261476887
    Selenium-Binding Protein 1 Deficiency Inhibits the Antitumor Immunity of Dendritic Cells.
    Shuang Han, Yi Li, Jie Meng, Jie Dai, Zhu Zeng, Yi Jia.
       AIMS: Selenium-binding protein 1 (SELENBP1) correlates positively with the prognosis of patients with colitis and colon cancer. SELENBP1-deficient dendritic cells (DCs) promote regulatory T cell differentiation and exert direct immunomodulatory functions. This study aimed to investigate whether SELENBP1-deficient DCs mediate antitumor immune function by affecting CD8+ T cell activation or exhaustion.
    RESULTS: Our findings revealed that SELENBP1 deficiency in mice accelerates colon cancer progression, characterized by reduced numbers of activated DCs and cytotoxic CD8+ T cells, increased intratumoral exhaustion-related factors, and impaired CD8+ T cell tumor-killing capacity. Adoptive-transfer experiments showed that SELENBP1 deficiency impairs DC antitumor activity, which may be associated with decreased intratumoral DCs, reduced cytotoxic CD8+ T cells, and increased dysfunctional T cell phenotypes. Moreover, in vitro cell experiments showed that the phosphatidylinositol 3-kinase/protein kinase B and hypoxia-inducible factor-1-alpha pathways are involved in DC migration as well as DC-mediated phenotypic dysfunction of CD8+ T cells. In addition, SELENBP1 expression in conventional DCs correlated positively with cytotoxic CD8+ T cells.
    INNOVATION: This study is the first to investigate the antitumor immune function of SELENBP1 in DCs.
    CONCLUSION: In vitro experiments showed that SELENBP1 deficiency impairs DC migration and maturation, resulting in decreased cytotoxic CD8+ T cells and increased dysfunctional T cell phenotypes. This phenomenon may underlie the accelerated colon tumor progression observed upon global SELENBP1 ablation or adoptive transfer of SELENBP1-deficient DCs. In brief, SELENBP1 deficiency impairs DC-mediated antitumor immune function. Antioxid. Redox Signal. 00, 000-000.
    Keywords:  T cell exhaustion; antitumor immunity; dendritic cell; selenium-binding protein 1
    DOI:  https://doi.org/10.1177/15230864261476887
  12. Cancer Lett. 2026 Aug 03. pii: S0304-3835(26)00536-7. [Epub ahead of print]659 218772
    Tumoral AMER1 driven dopamine synthesis triggers cancer cell pyroptosis and licenses CD8+ T cell immunity in colorectal cancer.
    Jun Long Dang, Qi Hu, Yang Lu, Jie Wang, Xiaoxue Li, Yixiong Chen, Jun Zhao, Yu Liu, Julie Wang, Nianke Zang, Li Zhou, Xiaolan Zhong, Wanglin Li, Song Guo Zheng.
      While classical tumor suppressors in colorectal cancer (CRC) are predominantly recognized for restraining cell-autonomous proliferation, their extrinsic mandate in orchestrating the tumor immunometabolic niche remains poorly defined. Clinically, we document that APC membrane recruitment protein 1 (AMER1) downregulation correlates with advanced progression and cytotoxic CD8+ T cell spatial exclusion in CRC patients. Using parallel homograft models in diverse host immune backgrounds, we show that tumoral AMER1 confers robust in vivo tumor-suppressive effects that are dependent on a fully functional immune system. Single-cell RNA sequencing reveals that tumoral AMER1 enrichment actively preserves CD8+ T cell effector stemness by expanding the CXCR5+ precursor exhausted subset (Tpex) across regional lymph nodes and primary tumor microenvironments. Integrated multi-omics and biochemical tracking identify dopamine (DA) as the conserved neurometabolic effector driving this niche remodeling. Mechanistically, AMER1 physically binds and rescues dopa decarboxylase (DDC) from post-translational degradation to sustain tumoral DA secretion; conversely, AMER1 loss creates a localized DA void. Cell-autonomously, tumoral DA accumulation triggers gasdermin D (GSDMD)-dependent tumor pyroptosis. Therapeutically, local DA administration halts multi-lineage carcinoma progression by reversing CD8+ T cell terminal exhaustion and reinforcing central memory differentiation. Collectively, our findings redefine AMER1 as a critical immunometabolic gatekeeper and establish neurotransmitter metabolic bypassing as a promising therapeutic strategy for CRC.
    Keywords:  AMER1/WTX; CD8(+) T cell stemness; Colorectal cancer; Dopamine decarboxylase; Neuro-immunometabolism; Tumor pyroptosis
    DOI:  https://doi.org/10.1016/j.canlet.2026.218772
  13. Nat Rev Rheumatol. 2026 Aug 03.
    Metabolic exhaustion and immune ageing in rheumatoid arthritis.
    Cornelia M Weyand, Jörg J Goronzy.
      Rheumatoid arthritis (RA) disproportionately affects adults over 50 years of age, highlighting how age-related immune remodelling undermines tolerance and promotes autoreactivity. In later adulthood, immune cells progressively lose metabolic resilience because of impaired nutrient sensing, reduced metabolic flexibility and disrupted anabolic-catabolic balance. In RA, these vulnerabilities are compounded by mitochondrial insufficiency across innate and adaptive immune lineages, creating a state of nutrient deprivation characterized by NAD⁺ and ATP scarcity and diversion of carbon away from oxidative phosphorylation. Mechanistic studies identify this bioenergetic fragility as a core defect that limits cellular longevity and promotes inflammatory, non-apoptotic death pathways, including pyroptosis and PANoptosis. The hypoxic, nutrient-restricted synovial environment adds pressure that exceeds the diminished metabolic adaptability of aged immune cells. In RA T cells, accelerated mitochondrial injury initiates maladaptive stress responses, disrupts mitochondria-lysosome-endoplasmic reticulum communication and induces gasdermin D-dependent pore formation and inflammatory lysis. Synovial MerTK⁺ reparative macrophages undergo a parallel metabolic crisis, whereby autocrine C1q sensing activates mitochondrial SARM1, causing NAD⁺ degradation, ATP depletion and PANoptotic cell death. Together, these findings position ageing-associated metabolic exhaustion and organelle disintegration as unifying mechanisms that convert immune cells into tissue-damaging effectors and explain the heightened susceptibility to RA in older adults.
    DOI:  https://doi.org/10.1038/s41584-026-01402-5
  14. Pathol Res Pract. 2026 Aug 02. pii: S0344-0338(26)00291-8. [Epub ahead of print]287 156638
    Targeting T-cell exhaustion and tumour immune evasion: a review of emerging strategies.
    Leticija Saltis, Liew Jun Mun.
      Adoptive T-cell therapies and immune checkpoint blockade have produced durable remissions in selected malignancies, yet most patients still fail to achieve lasting benefit. Two convergent obstacles underlie much of this failure: T-cell exhaustion and tumour immune evasion. T-cell exhaustion arises from chronic antigen stimulation in the tumour microenvironment (TME) and spans a hierarchy from reversible, stem-like progenitor-exhausted cells to terminally exhausted cells with limited functional recovery, which is a transition epigenetically enforced by transcription factors such as TOX and the NR4A family. In parallel, tumours evade recognition by silencing antigen-presentation pathways, including MHC class I. This review discusses a complementary therapeutic strategy that addresses both obstacles: engineering T cells for greater durability in the TME through knockout of exhaustion-associated transcription factors, and reprogramming tumour cells with DNA methyltransferase (DNMTi) and histone deacetylase (HDACi) inhibitors to restore immunogenicity. We also consider emerging evidence that metabolic and neuro-immune features of the TME, including nerve-to-tumour mitochondrial transfer, may contribute to immune resistance in some tumour contexts. Importantly, we emphasise that most supporting evidence derives from CAR-T and murine systems, and that direct validation in TCR-engineered T-cell (TCR-T) platforms is still required. We further outline a personalised, biomarker-guided framework that integrates T-cell signatures, the epigenetic landscape of the tumour, and tumour innervation density to match combination therapy to the individual patient. Integrating exhaustion-resistant T cells with a reprogrammed, immunologically visible tumour may help address mechanisms of immune resistance and improve therapeutic outcomes.
    Keywords:  CAR-T; Epigenetics; T-cell exhaustion; T-cells; TCR-T; Tumour immune evasion
    DOI:  https://doi.org/10.1016/j.prp.2026.156638
  15. Exp Mol Med. 2026 Aug 06.
    Metabolic rewiring of the dendritic cell-T cell axis: tumour-derived barriers and therapeutic opportunities.
    Minkyu Cho, Minkyung Song.
      The tumour microenvironment imposes severe metabolic constraints that reshape anti-tumour immunity across the cancer-immunity cycle. Rather than serving merely as passive byproducts of tumour growth, tumour-derived metabolites and nutrient imbalances act as potent metabolic checkpoints-stage-specific barriers that disrupt the functional progression of dendritic cells (DCs) and T cells from antigen presentation to effective tumour clearance. In this review, we propose a framework that overlays the cancer-immunity cycle with major metabolic checkpoints, including glucose and amino acid competition, acidosis and lipid overload, to clarify how distinct metabolic stresses create immune bottlenecks at different stages of the anti-tumour response. We then discuss how distinct tumour metabolic phenotypes, characterized by high glycolysis, amino acid dependency or lipid dysregulation, generate local environmental stresses that differentially reprogram DC function and T cell fitness. Particular emphasis is placed on the DC-T cell axis as a critical site where multiple metabolic defects converge, destabilizing antigen presentation, co-stimulation and immunological synapse function. We further survey emerging therapeutic strategies aimed at restoring the DC-T cell axis and effective anti-tumour immunity, ranging from small-molecule metabolic inhibitors to metabolically engineered adoptive cell therapies designed to function in hostile microenvironments. Finally, we highlight emerging technologies such as single-cell and spatial multi-omics, real-time metabolic imaging and microphysiological systems that can resolve the spatiotemporal heterogeneity of tumour immunometabolism and support more precise immunometabolic interventions.
    DOI:  https://doi.org/10.1038/s12276-026-01798-w
  16. Research (Wash D C). 2026 ;9 1370
    Loss of SETD2-mediated H3K36me3 Drives CD8+ T Cell Exhaustion in Lung Cancer through CXCL-dependent PMN-MDSC Recruitment and Arginine Deprivation.
    Xuyu Gu, Junjie Zhu, Tao Ge, Keyi Chen, Yang Yang, Kaiqi Jin, Xinnan Xu.
      Immune evasion in lung cancer is tightly regulated by epigenetic mechanisms. This study identifies key epigenetic drivers of immune escape in lung cancer and elucidates how they remodel the tumor microenvironment to induce CD8+ T cell exhaustion. We performed a CRISPR-negative screen targeting 159 epigenetic regulators (mEpi driver library) in a mouse model of lung metastasis and used single-cell sequencing, cell-based experiments, and chromatin analyses to identify mechanisms of immune escape. SET domain-containing protein 2 (SETD2) emerged as a critical suppressor of immune evasion. Loss of SETD2 markedly increased lung colonization and metastasis in mice with intact T cells, whereas this effect disappeared after T cell depletion. Mechanistically, SETD2 recruited adenine-thymine-rich interaction domain-containing protein 2 (ARID2) to maintain a repressive chromatin state at genes encoding the chemokines C-X-C motif chemokine ligand 1, 2, and 5. Loss of the SETD2-ARID2 axis increased secretion of these chemokines and recruited polymorphonuclear myeloid-derived suppressor cells, which inhibit T cell responses. These cells increased expression of free fatty acid receptor 2 (FFAR2), depleted arginine from the tumor environment, and impaired signaling required for T cell activation, driving cytotoxic T cells into terminal exhaustion. Depleting polymorphonuclear myeloid-derived suppressor cells or conditionally deleting FFAR2 in these cells restored T cell function and reduced metastasis of SETD2-deficient tumors. These findings show that loss of SETD2 creates an arginine-depleted, immunosuppressive tumor environment through a chemokine-FFAR2 pathway, revealing an epigenetic-metabolic immune checkpoint that may inform combination treatments for lung cancer.
    DOI:  https://doi.org/10.34133/research.1370
  17. Cell Rep. 2026 Aug 05. pii: S2211-1247(26)00865-X. [Epub ahead of print]45(8): 117787
    Inhibitory TIGIT signaling is dependent on T cell receptor activation.
    William H Zammit, Lucy J Le Maistre, Thomas A E Elliot, Stuart A Cain, Martin J Humphries, Daniel M Davis, Jonathan D Worboys.
      The immune checkpoint receptor T cell immunoreceptor with Ig and ITIM domains (TIGIT) can signal via cytoplasmic motifs to regulate T cell function. The signaling molecules that mediate inhibitory TIGIT signaling and its regulation in T cells remain poorly defined. Here, proximity proteomics is employed to define TIGIT-proximal proteins upon CD155 engagement, identifying several that are ligation-specific, including those involved in signaling (Grb2 and SOS1), cytoskeletal regulation (CD2AP and SdcBP), and endocytosis (IST1 and SNX3). Through crosslinking followed by immunoprecipitation, we show that TIGIT and CD2AP directly interact, representing a novel association. A TIGIT mutant (Y225A/Y231A) incapable of inhibitory signaling prevents recruitment of these proteins. Strikingly, T cell receptor (TCR) stimulation is essential for TIGIT to engage with these pathways. Mechanistically, phosphorylation of TIGIT requires both CD155 ligation and TCR activation, resulting in its signaling and internalization. TCR activation-dependent TIGIT signaling establishes a regulatory mechanism that limits checkpoint control to when functionally required.
    Keywords:  AND gate; CD155; CD2AP; CP: immunology; T cell; TIGIT; immune checkpoint; immune synapse; logic gating; proximity labeling; signaling
    DOI:  https://doi.org/10.1016/j.celrep.2026.117787
  18. Adv Sci (Weinh). 2026 Aug 03. e76963
    METTL7A Downregulation Drives SLC1A5-Mediated Glutamine Competition to Promote Tumor Proliferation and Suppress CD8+ T Cell Immunity in Gastric Cancer.
    Mingjun Sun, Shuwei Dang, Dazhi Zhou, Lixian Ding, Xun Sun, Wei Suo, Jirui Niu, Qingzhu Yang, Zhicheng Zhang, Yanyan Sun, Jinxing Li, Zhongsheng Chen, Tao Ban, Yingji Wang, Tianzhu Li, Ming Liu, Guodong Li.
      Tumor metabolic dysregulation is a critical determinant of tumor progression and response to immunotherapy. Aberrant glutamine metabolism is a hallmark of gastric cancer (GC). However, beyond fueling GC cell anabolism, its role in remodeling the immunosuppressive tumor microenvironment remains poorly understood. Here, we show that GC cells overexpress solute carrier family 1 member 5 (SLC1A5) to drive glutamine accumulation, which not only promotes their own proliferation but also reduces glutamine availability to CD8+ T cells, thereby suppressing antitumor immunity. These dual effects cooperatively drive GC progression. Mechanistically, loss of methyltransferase-like protein 7A (METTL7A) stabilizes SLC1A5 mRNA by reducing its m6A modification. Concurrently, METTL7A deficiency increased N-glycosyltransferase β-1,4-galactosyltransferase 5 (B4GALT5) expression. B4GALT5 stabilizes SLC1A5 via N-glycosylation at the N212 site, which blocks K48-linked polyubiquitination and proteasomal degradation. We identify the natural flavonoid luteolin as an agent that upregulates METTL7A expression, which subsequently downregulates SLC1A5 expression and inhibits GC progression. Furthermore, luteolin significantly enhances the efficacy of anti-PD-1 therapy in GC. Collectively, our findings reveal that SLC1A5-mediated glutamine competition drives both tumor cell proliferation and immune evasion in GC, and suggest that targeting the METTL7A/SLC1A5 axis may represent a promising therapeutic strategy.
    Keywords:  CD8+ T cells; METTL7A; SLC1A5; glutamine competition
    DOI:  https://doi.org/10.1002/advs.76963
  19. Signal Transduct Target Ther. 2026 Aug 07. pii: 314. [Epub ahead of print]11(1):
    Post-translational modifications in metabolic reprogramming: implications for metabolic therapy and immunotherapy in cancer.
    Si-Jie Chen, Shi-Wei Yue, Yun-Pu Zhang, Hui-Fang Liang, Hai-Xin Wu, Xiao-Ping Chen, Bi-Xiang Zhang, Wei Zhang.
      Cancer metabolism is characterized by profound reprogramming, yet the mechanisms enabling rapid and precise adaptation remain incompletely understood. This review establishes post-translational modifications (PTMs) as the central processing unit of oncogenic metabolic reprogramming. PTMs execute a conserved three-tiered regulatory logic: they interpret oncogenic and environmental signals, command metabolic flux, and cement malignant phenotypes through epigenetic and feedback mechanisms. We systematically demonstrate how this PTM-driven logic governs key pillars of cancer metabolism-glucose, lipid, amino acid, and nucleotide utilization-and extends its command to critical cell fate execution programs, including mitochondrial dynamics, autophagy, and ferroptosis. Furthermore, we delineate how PTMs act as master regulators of immunometabolic reprogramming within the tumor microenvironment (TME), directly linking tumor metabolism to T cell exhaustion, myeloid cell polarization, and immune evasion. By integrating recent advances on the determinants and crosstalk of PTM networks, we describe how metabolic plasticity and heterogeneity are encoded at the PTM level, with metabolic gradients shaping distinct "PTM geographies" within tumors. Finally, we translate these insights into clinical prospects, highlighting PTM-based biomarkers, PTM-targeted drugs and emerging therapeutic strategies, including targeted protein degradation, PTM-targeted vaccines and dietary interventions. Deciphering this PTM-encoded program reveals a new landscape of therapeutic vulnerabilities, shifting the paradigm toward rationally targeting the fundamental computational logic that sustains tumors.
    DOI:  https://doi.org/10.1038/s41392-026-02862-7
  20. Biochem Pharmacol. 2026 Aug 05. pii: S0006-2952(26)00657-X. [Epub ahead of print] 118318
    Intranodal injection of PD1 antibody enhances memory T cell responses to improve the efficacy of neoantigen vaccines.
    Sen Hong, Shuling Huang, Sizhe Qin, Haiyue Yu, Mengqi Wang, Jingwen Shen, Xinyang Li, Chengxu Liu, Baorui Liu, Wei Ren, Yaohua Ke, Qin Liu.
      Cold tumors are resistant to neoantigen vaccines (NeoVac) combined with systemic anti-PD1 (aPD1) due to unalleviated T-cell exhaustion in tumor. Here, we found the exhaustion of T cells in tumor-draining lymph nodes (TdLNs) contributed greatly to the exhaustion of T cells in tumor, which could not be improved by systemic aPD1. Therefore, we developed a novel strategy for cold tumors: NeoVac combined with intranodal aPD1 injection (NeoVac + aPD1-i.n). This approach effectively impedes T cell exhaustion in TdLNs and promotes naive T-cell differentiation into central memory T cells (TCM), which further develop into non-exhausted, tumor-specific effector memory T cells (TEM) upon neoantigen stimulation to efficiently kill tumor cells. In CT26 colon cancer and B16F10 melanoma models, NeoVac + aPD1-i.n significantly reduced intratumoral PD1+ T-cell proportions, achieving tumor growth inhibition rates of 70.7% (CT26) and 94.3% (B16F10), with prolonged survival and no obvious adverse effects. By inducing tumor-specific immune response, aPD1-i.n overcomes the drug resistance of NeoVac in cold tumors, holding great clinical translation potential.
    Keywords:  Intranodal injection; Memory T cells; Neoantigen vaccines; PD1 antibody; Tumor-draining lymph nodes
    DOI:  https://doi.org/10.1016/j.bcp.2026.118318
  21. Front Immunol. 2026 ;17 1933173
    Correction: NOSIP overexpression promotes long-term persistence of CD8+ T cells during chronic infection.
    Shihui Li, Toshikatsu Tamai, Yui Shinzawa, Sotaro Fujisawa, Yamato Tanabe, Makoto Utsunomiya, Hidetoshi Nakagawa, Junko Kurachi, Miki Koura, Eishiro Mizukoshi, Makoto Kurachi.
      [This corrects the article DOI: 10.3389/fimmu.2026.1755657.].
    Keywords:  CD8+ T cells; CX3CR1 subset differentiation; NOSIP; PD-L1 blockade responsiveness; chronic antigen stimulation
    DOI:  https://doi.org/10.3389/fimmu.2026.1933173
  22. Sci Immunol. 2026 Aug 07. 11(122): eael0168
    PKM2 works "off the books" to drive effector T cell function in MS.
    Alexia Falle, Manu Rangachari.
      The noncanonical functions of PKM2 drive pathogenic T cell function in patients with MS.
    DOI:  https://doi.org/10.1126/sciimmunol.ael0168
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