bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2026–09–13
thirteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. CD8+ T cells kill tumors by proxy.
  2. In vivo genome-wide CRISPR screens identify FOXR1 as a suppressor of CD8+ T cell antitumor immunity.
  3. NAD+ Metabolic Reprogramming Drives CD8+ T Cells Senescence and Exacerbates Ulcerative Colitis.
  4. Interferon regulatory factors orchestrate CD8+ T cell function (Review).
  5. Activation of lipid synthesis following glycolysis is required for CD8+ T cells to acquire antitumor immune activity.
  6. Mitochondrial ATP promotes T cell differentiation through chromatin accessibility.
  7. Stem-like CD4 T cells in tumors: an emerging framework for antitumor immunity.
  8. Targeting LOXL4-driven matrix stiffening with acetyldigoxin restores CD8+ T cell function in lung cancer.
  9. Metabolic and epigenetic plasticity of tumor-associated macrophages shapes immunosuppressive outputs and immune checkpoint response.
  10. Exosomal miR-484 impairs CD8 + T cell homeostasis in sepsis through the YPEL1/Cyclin E axis.
  11. CAFs-mediated histone lactylation reprograms cholesterol metabolism in colorectal cancer to drive CD8+ T cell immunosuppression.
  12. Siglec-7 orchestrates mitochondrial dynamics and metabolic reprogramming to restrain human NK cell cytotoxic function.
  13. Tumor-associated neutrophils and macrophages differentially affect T cell biology in the head and neck cancer tumor microenvironment.
  1. Nat Immunol. 2026 Sep 09.
    CD8+ T cells kill tumors by proxy.
      
    DOI:  https://doi.org/10.1038/s41590-026-02664-7
  2. Proc Natl Acad Sci U S A. 2026 Sep 15. 123(37): e2534362123
    In vivo genome-wide CRISPR screens identify FOXR1 as a suppressor of CD8+ T cell antitumor immunity.
    Xue Yang, Han Ouyang, Henan Xu, Lingxiao Peng, Jianzhou Cui, Bin Zhang, Bo Huang, Chunmei Wang, Guideng Li, Xuetao Cao.
      T cell dysfunction critically limits the efficacy of T cell-based immunotherapies in solid tumors, yet the intrinsic regulators of T cell dysfunction remain incompletely understood. Through an in vivo genome-wide CRISPR screen in tumor-infiltrating CD8+ T cells, we identified Forkhead Box R1 (FOXR1) as a potent transcriptional suppressor of CD8+ T cell effector functions. Genetic ablation of FOXR1 significantly enhanced cytokine production and cytotoxic capacity in both murine and human CD8+ T cells, whereas its overexpression impaired T cell activation and effector molecule expression. Mechanistically, multiomics integration of RNA-seq, CUT&Tag-seq, and ATAC-seq revealed that FOXR1 binds directly to promoter regions of key effector genes, including IL2, GZMB, and PRF1, and represses their expression. Importantly, FOXR1 deletion in human anti-CD19 CAR T cells improved their efficacy against solid tumors, demonstrating that FOXR1 is a checkpoint of T cell effector function and targeting FOXR1 is a promising strategy to enhance CAR T cell efficacy against solid tumors.
    Keywords:  CAR T cell; FOXR1; T cell dysfunction; antitumor immunity; tumor-infiltrating T cells
    DOI:  https://doi.org/10.1073/pnas.2534362123
  3. Aging Cell. 2026 Sep;25(9): e70706
    NAD+ Metabolic Reprogramming Drives CD8+ T Cells Senescence and Exacerbates Ulcerative Colitis.
    Maolin Ye, Qi Zhou, Mingjia Kong, Suhan Zhao, Lingxi Lin, Lirong Chen, Jianghong Yu, Feifei Luo, Jie Liu, Jun Zhang.
      While immunosenescence is increasingly implicated in chronic inflammatory disorders, its precise pathogenic contribution to ulcerative colitis (UC) remains elusive. Here, we identify senescent CD8+ T cells as a distinct pathogenic population that exacerbates colitis, demonstrating that systemic senolytic treatment significantly attenuates disease severity. Mechanistically, nicotinamide adenine dinucleotide (NAD+) metabolic dysregulation triggers mitochondrial dysfunction and cytosolic mitochondrial DNA leakage, promoting CD8+ T cell senescence through the activation of the cGAS-STING signaling pathway. Spatial transcriptomic mapping reveals that senescent CD8+ T cells are enriched within mucosal niches experiencing NAD+ metabolic dysregulation. Crucially, this senescent-metabolic signature correlates with severe disease phenotypes and predicts non-response to biologic therapies in UC patients. Collectively, our findings uncover a critical NAD+-cGAS-STING axis driving T cell senescence, establishing the clearance of senescent immune cells as a promising therapeutic strategy for UC.
    Keywords:  NAD+; immunosenescence; inflammatory bowel disease; senolytic therapy
    DOI:  https://doi.org/10.1111/acel.70706
  4. Int J Mol Med. 2026 Nov;pii: 311. [Epub ahead of print]58(5):
    Interferon regulatory factors orchestrate CD8+ T cell function (Review).
    Fa-Xi Wang, Chun-Liang Yang, Shan-Jie Rong, Qi-Jie Chen, Xiong-Tao Yue, Fei Sun.
      The fate of CD8+ T cells is dictated by epigenetic remodeling, metabolic rewiring and most critically, the transcriptional reprogramming that integrates diverse extracellular signaling pathways. Transcription factors (TFs) predetermine cell differentiation state and lineage‑specifying hub TFs are decisive for CD8+ T cell functional maturation. The present study aimed to summarize the indispensable roles of interferon regulatory factors (IRFs) in CD8+ T cell biology from early thymic development to the acquisition of distinct functional states. Alone or together with other TFs, IRFs are involved in the regulation of CD8+ T cell commitment, effector differentiation, memory maintenance and terminal exhaustion. In clinical practice, IRF family members hold potential as prognostic biomarkers and valuable therapeutic targets in CD8+ T cell‑associated immune disorders, such as tumors, transplant rejection, infection and autoinflammatory diseases.
    Keywords:  CD8+ T cell; cooperative binding; interferon regulatory factor; transcriptional regulation
    DOI:  https://doi.org/10.3892/ijmm.2026.5982
  5. Biochem Biophys Res Commun. 2026 Sep 05. pii: S0006-291X(26)01297-0. [Epub ahead of print]835 154533
    Activation of lipid synthesis following glycolysis is required for CD8+ T cells to acquire antitumor immune activity.
    Taisuke Hamada, Makoto Kuwahara, Hiroki Tokiwa, Waichi Yamamoto, Junpei Suzuki, Shunsuke Nomura, Yuko Matsuoka, Takahumi Matsushita, Sakiko Kitamura, Ayato Kawashima, Tasuku Nishihara, Masakatsu Yamashita.
      Activated CD8+ T cells undergo metabolic reprogramming and shift to aerobic glycolysis to fulfill their energy and biosynthetic demands. However, the downstream pathways linking glycolytic flux to potent antitumor immunity remain unclear. In this study, we used a T-cell-specific phosphoglycerate mutase 1 (Pgam1)-deficient mouse model to demonstrate that accelerated lipid synthesis induced by glycolysis is necessary for CD8+ T cells to acquire antitumor activity. Pgam1 deficiency severely impaired antitumor activity and intratumoral infiltration in the MC38-OVA tumor model. Transcriptomic profiling of Pgam1-deficient CD8+ T cells activated in vitro revealed that Pgam1 deficiency caused a marked reduction in the lipid biosynthetic program and altered lipid composition. We found that in Pgam1-deficient CD8+ T cells, TCR stimulation dose not induce the upregulation of the Srebf1 and Srebf2 genes, which encode the master transcription factors Srebp1 and Srebp2, respectively, that regulate lipid synthesis. Pharmacological inhibition of SREBPs by fatostatin attenuated effector functions, such as TCR-induced proliferation, cytokine production, and cytotoxicity. These findings indicate that the activation of SREBP-dependent lipid synthesis pathways, which follow glycolysis, is important for the acquisition of antitumor activity by CD8+ T cells.
    Keywords:  Antitumor activity; CD8(+) T cells; Glycolysis; Lipid synthesis; SREBP
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154533
  6. Cell. 2026 Sep 11. pii: S0092-8674(26)00996-7. [Epub ahead of print]
    Mitochondrial ATP promotes T cell differentiation through chromatin accessibility.
    Charles Ng, Tak Shun Fung, Dayi Li, Korbinian N Kropp, Luis F Somarribas Patterson, Alexandria Markovitz, Daniel N Weinberg, Olivia Jones, Ji-Young Kim, Guoan Zhang, Richard Koche, Mara Monetti, Huayuan Tang, Yun He, Zhengshuang Xu, Xin Cai, Ziqi Yu, Geetha Bhagavatula, Sean P Colgan, Ya-Hui Lin, Zhuoning Li, Elizabeth M Steinert, Christopher A Klebanoff, Santosha A Vardhana, Navdeep S Chandel, Lin Wu, Craig B Thompson.
      Immune elimination of chronic infection or cancer requires cytotoxic CD8+ T cells that adopt and maintain an effector phenotype. Cytotoxic T cell function is a bioenergetically demanding process. Here, we report the ability of D-α-hydroxybutyrate (DAHB) to act as a signaling molecule that increases mitochondrial ATP production and drives the conversion of proliferating T cells into cytotoxic effector cells. DAHB signaling switches ATP production from glycolysis to oxidative phosphorylation supported by fatty acid oxidation. This conversion elevates the level of a phosphagen, phosphocreatine (PCr). Both the PCr bioenergetic reserve and oxidative phosphorylation were required for T cell effector differentiation. DAHB-induced CD8 effector gene transcription was coupled to bioenergetics by BAF-complex-dependent remodeling of chromatin at effector loci. DAHB-enhanced CD8+ T cell antitumor activity both in vitro and in vivo. Together, these findings link cellular bioenergetics to the regulation of chromatin accessibility and gene expression required to support effector function.
    Keywords:  BAF; CD8 T cell effector function; D-alpha-hydroxybutyrate; OXPHOS; chromatin remodeling; creatine; phosphocreatine; tumor immunology
    DOI:  https://doi.org/10.1016/j.cell.2026.08.023
  7. Front Immunol. 2026 ;17 1853163
    Stem-like CD4 T cells in tumors: an emerging framework for antitumor immunity.
    Jiaxiang Xu, Yunchao Yang, Jun Zhang, Yue Zhang.
      Recent studies have identified antigen-experienced TCF1+PD-1+ lineage-negative (lin-) CD4 T cells in several tumor types. Strictly, stemness requires durable self-renewal and multipotent output demonstrated at the single-cell level; these criteria have not yet been established for an individual tumor-associated CD4 T cell. Operationally, this review uses "stem-like CD4 T cells" for TCF1+PD-1+ lin- populations that lack canonical terminal TH1, TH2, TH17, and Treg commitment programs and show population-level persistence and multilineage output. Pending single-cell lineage tracing, these populations are best regarded as candidate progenitor-like states. Within the tumor microenvironment, their differentiation trajectory may influence antitumor immunity. Treg-mediated suppression, TGF-β signaling, metabolic stress, and limited IL-12 can restrain effector differentiation, whereas release of these constraints can permit TH1 output, CD8-supporting activity in tumor-draining lymph nodes, and direct MHC class II-restricted antitumor effects in selected models. Direct tumor evidence remains concentrated in a limited set of studies, while infection, autoimmunity, transplantation, and CD8 research provide contextual or cross-lineage support. This review therefore presents stem-like CD4 biology as an emerging framework and distinguishes established observations from working models.
    Keywords:  T cell differentiation; T cell stemness; TCF1; cancer immunotherapy; immune checkpoint blockade; stem-like CD4 T cells; tumor immunity; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1853163
  8. Sci Adv. 2026 Sep 11. 12(37): eaef1694
    Targeting LOXL4-driven matrix stiffening with acetyldigoxin restores CD8+ T cell function in lung cancer.
    Xuyu Gu, Yifei Zhu, Li Xu, Xinnan Xu, Kaiqi Jin, William C Cho, Qiyu Fang.
      Extracellular matrix (ECM) stiffness is known to impair T cell function, yet the underpinning molecular cascade remains undefined. This paper investigates the role of lysyl oxidase-like 4 (LOXL4) in ECM stiffening and CD8+ T cell function in lung cancer. Loxl4 knockout and mouse recombinant LOXL4 protein systems, along with Piezo1, Ybx1, Acly, and Kat2a conditional knockout mouse models were established. ECM stiffness was measured by atomic force microscopy, and T cell exhaustion markers were analyzed using flow cytometry. RNA sequencing, ATAC-seq, CUT&Tag, chromatin immunoprecipitation-quantitative polymerase chain reaction, and luciferase assays were used to explore the underlying molecular mechanisms. Molecular docking was performed to explore Food and Drug Administration-approved agents targeting LOXL4. The results demonstrated that tumor-derived LOXL4 stiffened the ECM, which activates the mechanosensor Piezo1 in CD8+ T cells, triggering Ca2+ influx and downstream FAK1-YAP1 signaling. Nuclear YAP1 transactivated YBX1, which recruited the metabolic enzyme ACLY and the histone acetyltransferase KAT2A to exhaustion gene loci, epigenetically reinforcing terminal exhaustion. Conditional knockout of Piezo1, Ybx1, Acly, and Kat2a in murine CD8+ T cells abolished stiffness-induced exhaustion and suppressed tumor growth. Acetyldigoxin was identified as a high-affinity LOXL4 inhibitor. It softened the ECM, disrupted the mechanosignaling-epigenetic axis, reversed CD8+ T cell exhaustion, and synergized with anti-PD-1 blockade to achieve durable tumor regression. In conclusion, this study uncovers a mechanotransduction-to-epigenetic pathway where LOXL4-driven matrix stiffening induces CD8+ T cell exhaustion. Repurposing acetyldigoxin as a LOXL4-targeted therapy offers a promising clinical strategy to overcome ECM-mediated immunotherapy resistance in lung cancer.
    DOI:  https://doi.org/10.1126/sciadv.aef1694
  9. Biochim Biophys Acta Rev Cancer. 2026 Sep 08. pii: S0304-419X(26)00174-5. [Epub ahead of print]1881(6): 189702
    Metabolic and epigenetic plasticity of tumor-associated macrophages shapes immunosuppressive outputs and immune checkpoint response.
    Jinghao Pan, Boyang Li, Lucy Yue Lau, Zehao Hong, Yi Chen.
      Immune checkpoint blockade (ICB) has transformed cancer therapy, but durable responses are frequently limited by tumor microenvironment-driven resistance. Tumor-associated macrophages (TAMs) are central mediators of this process because they sense metabolic stress and convert it into immunosuppressive programs that restrict antigen presentation, effector T cell entry, and cytotoxic function. This review conceptualizes the tumor microenvironment as a metabolic ecosystem shaped by hypoxia, lactate accumulation, acidosis, nutrient competition, lipid-rich niches, and amino-acid scarcity. We propose a context-dependent state-transition model in which these pressures are decoded by interconnected nutrient- and stress-sensing pathways, integrated through mitochondrial bioenergetic and redox adaptation, and translated by metabolite-dependent chromatin remodeling into persistent TAM functional programs that constrain the depth and durability of ICB responses. We further link glucose, lipid, and amino-acid metabolic circuitry to checkpoint resistance and propose therapeutic leverage tiers and biomarker layers for TAM metabolic reprogramming combined with ICB. This framework highlights actionable routes to overcome myeloid-driven immune resistance.
    Keywords:  Epigenetic imprinting; Immune checkpoint blockade; Immunometabolism; Metabolic plasticity; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189702
  10. Acta Biochim Biophys Sin (Shanghai). 2026 Sep 11.
    Exosomal miR-484 impairs CD8 + T cell homeostasis in sepsis through the YPEL1/Cyclin E axis.
    Jiaqian Ling, Zhouyi Chen, Yile Zhou, Guangshan Jin, Yuanyang Chen, Jianxin Dong, Xia Sun, Yi Shi, Hao Fang.
      Sepsis induces profound CD8 + T cell dysfunction, contributing to immunosuppression and poor outcomes. Exosomes mediate intercellular communication during sepsis, but the role of exosomal microRNAs in regulating CD8 + T cell homeostasis remains unclear. Sepsis patients and healthy controls are prospectively enrolled to investigate plasma exosomes and CD8 + T cell responses. Exosomes from sepsis patients (SE) promote CD8 + effector differentiation and dysregulate cell cycle progression compared to those from healthy donors (HE). miRNA sequencing identifies miR-484 as the most upregulated miRNA in SE. Functionally, SE-derived miR-484 suppresses YPEL1 expression in CD8 + T cells, leading to increased Cyclin E levels and aberrant cell cycle distribution. Inhibition of miR-484 restores YPEL1 and normalizes Cyclin E expression, which is associated with a reversal of the sepsis exosome-induced bias toward CD8 + effector differentiation. Our findings reveal that exosomal miR-484 impairs CD8 + T cell homeostasis in sepsis by targeting the YPEL1/Cyclin E pathway, highlighting a potential mechanism for immune dysregulation and a target for intervention.
    Keywords:  CD8 T cell homeostasis; Cyclin E; YPEL1; exosomal microRNA; miR-484; sepsis
    DOI:  https://doi.org/10.3724/abbs.2026107
  11. J Pathol. 2026 Sep 08.
    CAFs-mediated histone lactylation reprograms cholesterol metabolism in colorectal cancer to drive CD8+ T cell immunosuppression.
    Huachi Li, Jun Hu, Lei Huang, Zihao Wang, Haoran Tao, Feng Cao, Min Xie.
      The progression of colorectal cancer (CRC) is critically regulated by cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME), yet the specific molecular mechanisms by which CAFs influence CRC remain unclear. This study reveals the mechanism by which CAFs promote CRC malignant progression and immune suppression through metabolic reprogramming. Findings indicate that lactate secreted by CAFs induces lactylation modifications of histone H3K9La and H3K18La, thereby upregulating the expression of key cholesterol synthesis enzymes DHCR7 and CYP51A1, which in turn enhances the malignant properties of CRC cells. In vivo and in vitro experiments confirm that inhibiting DHCR7 significantly reverses CAF-mediated tumor promotion. More importantly, this study revealed that CAF-induced CRC cells with elevated cholesterol metabolism deliver DHCR7 to CD8+ T cells via exosomes, thereby triggering mitochondrial dysfunction and driving the cellular senescence process. This senescence manifests as reduced IFN-γ secretion capacity and enhanced senescence-associated secretory phenotype (SASP). In summary, this study systematically elucidates the central role of the CAF-CRC cell-CD8+ T cell regulatory axis: CAF-derived lactate modulates cholesterol metabolism in CRC cells via histone lactylation. Subsequently, CRC cells with enhanced cholesterol metabolism deliver DHCR7 to CD8+ T cells via exosomes, inducing mitochondrial dysfunction, which in turn leads to CD8+ T-cell senescence and immunosuppression. This provides a new theoretical foundation and therapeutic rationale for metabolic-immune combination strategies in CRC. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
    Keywords:  CAFs; CD8+ T cells; CRC; DHCR7; cholesterol metabolism; histone lactylation; immunosuppression
    DOI:  https://doi.org/10.1002/path.70119
  12. J Biol Chem. 2026 Sep 08. pii: S0021-9258(26)02415-4. [Epub ahead of print] 113543
    Siglec-7 orchestrates mitochondrial dynamics and metabolic reprogramming to restrain human NK cell cytotoxic function.
    Shih-Chi Su, Nai-Ting Tsao, Tzu-Ling Wang, Yi-Chen Shih, Yuh-Ching Twu.
      Natural killer (NK) cells are innate lymphocytes that directly eliminate tumor and virus-infected cells by integrating signals from activating and inhibitory receptors, and their effector functions are tightly coupled to cellular metabolism. Given that the inhibitory receptor PD-1 reprograms T cell metabolism to shape functional fate, the bioenergetic consequences of inhibitory receptor engagement on human NK cells remain largely unexplored, particularly for sialic acid-binding immunoglobulin-like lectin (Siglec-7), a glyco-immune checkpoint receptor. Here, we investigated metabolic programs and effector functions associated with Siglec-7 expression and antibody-mediated Siglec-7 ligation in primary NK cells and NK-92MI cells. Siglec-7POS NK cells exhibited selectively impaired CD107a degranulation under glycolytic and oxidative phosphorylation inhibition, whereas Siglec-7NEG cells remained relatively resistant, indicating distinct energetic wiring between these subsets. Engagement of Siglec-7 by an agonistic antibody induced mitochondrial fission with altered Drp1 phosphorylation, transient mitochondrial depolarization, and broadly suppressed mitochondrial respiration, while concurrently enhancing glycolytic capacity, consistent with a dual metabolic shift upon Siglec-7 ligation. In contrast, sustained Siglec-7 expression in NK-92MI-S cells was associated with globally enhanced mitochondrial respiratory capacity, indicating that sustained Siglec-7 expression and short-term treatment with an agonistic anti-Siglec-7 antibody were associated with distinct metabolic profiles in NK cells. Furthermore, Siglec-7POS NK cells showed increased accumulation of autophagic vacuole, reduced proliferation, and heightened apoptotic susceptibility compared with Siglec-7NEG counterparts. Collectively, these findings support an association between Siglec-7 status, mitochondrial homeostasis, and metabolic fitness in NK cells, with Siglec-7NEG cells retaining a metabolically robust, cytotoxic phenotype.
    DOI:  https://doi.org/10.1016/j.jbc.2026.113543
  13. J Leukoc Biol. 2026 Sep 08. pii: qiag122. [Epub ahead of print]
    Tumor-associated neutrophils and macrophages differentially affect T cell biology in the head and neck cancer tumor microenvironment.
    Xi Wang, Stefan Kasper, Hendrik Winkel, Kirsten Bruderek, Michael Pogorzelski, Eric Deuss, Sarah Theurer, Stephan Lang, Cornelius H Kürten, Sven Brandau.
      Intra-tumoral T cell activity is required for effective anti-tumor immune responses and is partly regulated by tumor-associated neutrophils and macrophages. Here, we investigated the spatial context of neutrophil/macrophage interactions with CD8+ T cells in head and neck squamous cell carcinoma. Using multiplex immunofluorescence staining of biopsies from 14 patients, we analyzed neutrophils, macrophages, and CD8+ T cells within tumor nests and stromal compartments. All three cell types were enriched in the stroma. To characterize spatial immune niches, we defined regions enriched for each cell type and analyzed their overlap. CD8+ T cells showed spatial exclusion from neutrophils, whereas macrophages co-localized with CD8+ T cells. In regions enriched for both neutrophils and CD8+ T cells, neutrophils were associated with reduced CD8+ T cell proliferation, potentially caused by contact-dependent suppression. These findings demonstrate that neutrophils and macrophages differentially shape CD8+ T cell distribution and activity within the head and neck cancer microenvironment.
    Keywords:  immune niche; myeloid-derived suppressor cells; spatial analysis; stroma; tumor core
    DOI:  https://doi.org/10.1093/jleuko/qiag122
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