bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2026–11–01
48 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. The Y chromosome gene KDM5D restrains CD8+ T cell antitumor immunity through TCR and cholesterol-exhaustion programs.
  2. Broken Engines of Immunity: Mitochondrial Dysfunction in T Cells Across Cancer and Complex Pathologies.
  3. Nutrient-sensitive histone propionylation regulates T cell fate and function.
  4. Glucose restriction induced by intermittent fasting promotes alternative metabolic fluxes leading to memory CD8+ T cell development.
  5. From Dysfunction to Differentiation: A New Paradigm of T Cell Exhaustion.
  6. hnRNPA2B1 sustains antitumor T cell immunity and enhances cancer immunotherapy through IDR-dependent stabilization of chromatin-regulatory transcripts.
  7. The fate of cysteine's sulfur in CD8+ T cell function.
  8. Time-Encoded Ligand Presentation via a Magnetically Actuated Hydrogel Mitigates T Cell Exhaustion.
  9. Beyond Exhaustion: The RNA Regulatory Layer of Tissue-Instructed T Cell Dysfunction.
  10. Deoxycorticosterone Reshapes CD8+ T Cell State and Effector Function Through Distinct Metabolic Signaling Programs.
  11. One-carbon metabolism sustains effector T cell function through cell-surface glycosylation.
  12. The Notch signaling pathway is a master regulator of CD8+ T cell exhaustion and differentiation during chronic infection.
  13. T-cell metabolic reprogramming in systemic lupus erythematosus: linking intracellular metabolism to effector differentiation and senescent-like/exhausted-like states.
  14. p53 activation via pharmacologic MDM2 inhibition constrains exhaustion and enhances antitumor function of human CD8+ T cells.
  15. Single-cell multi-omics reveals archetypal regulatory programs shared across T cell subsets.
  16. Metabolic Dysfunction and T-Cell Exhaustion in Colorectal Cancer: Mechanisms, Microenvironment Remodeling, and Therapeutic Opportunities.
  17. Neutrophil-Derived Arg1 Impairs CD8+ T Cell Activity in Sepsis Through mTOR-Mediated Mitochondrial Dysfunction.
  18. T cell metabolic ageing as a factor for therapeutic research.
  19. Spermidine disrupts mitochondrial respiration and redox homeostasis in aged CD44+ CD49d- CD8+ T cells.
  20. Immunosenescence in Aging and Cancer: Molecular Mechanisms, Tumor Microenvironment Remodeling, and Therapeutic Implications.
  21. Interferons and STAT1 dynamically modulate integrated stress response outcomes in CD8 T cells.
  22. Metabolically Activated Proteostasis Regulators Reduce Differentiation of CD4+ TH17 Cells.
  23. Targeting Immune Cell Metabolism for Tolerance.
  24. Hypoxic conditioning of neuroblastoma cells promotes CD8+ T-cell dysfunction through the HIF-1α/PD-L1 axis.
  25. Reconciling CD8 T cell subsets: GZMK+, cytotoxic, resident memory, exhausted, and other CD8 T cells in blood and tissue.
  26. SLC3A2 Drives an Immunosuppressive Metabolic Axis that Limits Oncolytic Virotherapy Efficacy.
  27. An epigenetic regulator that promotes NK cell function.
  28. Arginine rewires eIF4F translation initiation to overcome fever-induced CAR T cell dysfunction.
  29. Adaptive immune plasticity in MASH: Functional states, pathological consequences, and regulatory mechanisms.
  30. Tumour assembloids recapitulate tumour-CAF-T cell crosstalk in renal cancer.
  31. Granzyme K-expressing CD8+ T cells, complement activation and histotoxic immunity.
  32. Senescent Mesenchymal Stromal Cells Drive Stem Cell Aging Through Dysregulated Chemokine Synthesis.
  33. Metabolic Rewiring of GPC3-Targeted CAR T Cells Expressing IL-15 and HER2-Targeted CAR T Cells via the ADA1-CD26 Axis Promotes Tumor Infiltration and Limits Systemic Toxicities.
  34. BAZ2A-induced epigenetic states in cancer cells fuel palmitate accumulation in the tumor microenvironment driving CAR-T cell exhaustion.
  35. Targeting exosomal circSENP5 prevents immune escape of macrophages in pMMR-CRC via regulating mitochondrial metabolism.
  36. SIRPγ promotes CD8⁺ T cell exhaustion via metabolic-epigenetic reprogramming in tuberculous pleural effusion.
  37. A Narrative Review of Nanomedicine in Cancer Therapy: Modulating Metabolic Reprogramming to Enhance Immunotherapy.
  38. SIRT2 in metabolism, aging, and longevity.
  39. Adenosylhomocysteinase drives epigenetic and metabolic reprogramming in ZFTA-RELA ependymoma.
  40. Hepatitis C viral variants bear signatures of de novo CD8+ T cell and antibody pressure after spontaneous postpartum viral suppression.
  41. Neutrophil metabolic heterogeneity as a novel target in diseases.
  42. Targeting GALE harnesses γδ T cells for cancer immunotherapy.
  43. Spatiotemporal immune remodeling by light at night uncovers an adaptive immune signature linked to tumor progression and anti-PD-1 non-response.
  44. Attenuating NKG2D stimulation reshapes intratumoral NK cell functional state to enhance persistence and anti-tumor efficacy.
  45. A mechanistic basis for CD8+ T cell expansion sensitivity as a predictor of HIV post-treatment control.
  46. Generation of Murine Chimeric Antigen Receptor T Cells for Adoptive T Cell Therapy for Melanoma.
  47. [Editorial].
  48. Repeated malaria exposure reprograms Vδ2+ γδ T cell chromatin accessibility and immune function toward a reversible hyporesponsive state.
  1. bioRxiv. 2026 Sep 01. pii: 2026.07.23.740424. [Epub ahead of print]
    The Y chromosome gene KDM5D restrains CD8+ T cell antitumor immunity through TCR and cholesterol-exhaustion programs.
    Jiexi Li, Chi Yin Ching, Aviad Ben-Shmuel, Paulino Tallón de Lara, Jingjing Liu, Jiang Shan, Chaohao Li, Ziyuan Zhang, William Huaiyang Wu, Max Slotnik, Xiaotian Wang, Raul Caballero Montes, Abhinav K Jain, Nicholas Hornstein, Fadl Zeineddine, Mohammad Zeineddine, Scott Eric Woodman, Natividad Roberto Fuentes, Denise J Spring, John Paul Shen, Scott Kopetz, Ronald A DePinho.
      Sex differences in immunity shape cancer risk, autoimmunity, and responses to immunotherapy, yet the sex-chromosome genes that regulate antitumor T cell function remain incompletely defined. Here, we identify the Y chromosome-encoded KDM5D histone demethylase as a male-specific suppressor of CD8+ T cell antitumor immunity. In murine colorectal cancer (CRC) models, male CD8+ T cells displayed reduced cytokine production, proliferation, cytotoxicity, TCRβ abundance, and proximal TCR signaling relative to female CD8+ T cells. CRISPR-RNP-mediated KDM5D depletion in male CD8+ T cells enhanced effector function, increased TCRβ expression, augmented TCR signaling, and improved tumor control after adoptive transfer. Transcriptomic and functional analyses further linked KDM5D to cholesterol biosynthesis and exhaustion-associated programs, with KDM5D depletion reducing SREBP2/XBP1-associated cholesterol and exhaustion signatures. Correspondingly, human CRC single-cell analyses supported the clinical relevance of this axis, showing enrichment of exhausted and cholesterol-associated CD8+ T cell states in male tumors. Pharmacologic inhibition of cholesterol biosynthesis with lovastatin partially attenuated select exhaustion-associated markers in male CD8+ T cells and delayed tumor growth in vivo. Together, these findings define KDM5D as a sex chromosome-encoded regulator of male CD8+ T cell dysfunction and point to cholesterol-exhaustion programs as a potential therapeutic vulnerability in male CRC.
    DOI:  https://doi.org/10.64898/2026.07.23.740424
  2. Eur J Immunol. 2026 Oct;pii: e70300. [Epub ahead of print]56(10):
    Broken Engines of Immunity: Mitochondrial Dysfunction in T Cells Across Cancer and Complex Pathologies.
    Carolina Brescia, Giuseppe Viglietto, Rosario Amato.
      Mitochondria have traditionally been viewed as the cellular 'powerhouses' responsible for energy production; however, they also play essential roles in a wide range of cellular processes, including macromolecule biosynthesis and the regulation of apoptosis. Accumulating evidence highlights their importance in immune regulation, particularly through their influence on T cell activation, proliferation, and effector function. In addition to ATP generation, mitochondria regulate redox and calcium homeostasis and produce metabolites that modulate the transcriptional and epigenetic programs of immune cells. Upon antigen recognition, T lymphocytes undergo marked metabolic reprogramming, characterised by increased glycolysis while preserving mitochondrial metabolism as a critical pathway. Mitochondrial dysfunction disrupts intracellular signalling and contributes to T cell exhaustion in diverse pathological contexts, including cancer and chronic viral infections. Consequently, strategies aimed at restoring mitochondrial function are emerging as promising therapeutic approaches to correct immune dysfunction driven by impaired T cell responses. Importantly, these alterations should not be interpreted solely as downstream consequences of chronic immune stimulation; rather, mitochondrial dysfunction can actively determine T-cell fate, stabilise exhaustion-associated programs, and define the extent to which dysfunctional T cells remain therapeutically reversible. This review first outlines mitochondrial structure, bioenergetics, dynamics, and quality-control pathways and then examines how these processes are remodelled across naïve, effector, circulating-memory, tissue-resident-memory, and exhausted T-cell states. It subsequently integrates evidence from cancer, chronic viral infection, and ageing and evaluates mitochondria-directed strategies for restoring T-cell function.
    Keywords:  T cell; T‐cell exhaustion; cancer; metabolism; mitochondria; mitochondrial dysfunction
    DOI:  https://doi.org/10.1002/eji.70300
  3. bioRxiv. 2026 Oct 06. pii: 2026.10.01.756002. [Epub ahead of print]
    Nutrient-sensitive histone propionylation regulates T cell fate and function.
    Alison Jaccard, Kelly Rome, Qihua Yang, Shuo Zhang, Noah Ford, Adam Chatoff, Tran Ngoc Van Le, Michael Noji, Andrea Andress Huacachino, Stephanie Stransky Lauar, Carlos Pondevida, Krittin Trihemasava, Laura V Pinheiro, Sanat Bhadsalve, Eun Kyung Ko, Charles Salinas, Mariola M Marcinkiewicz, Brian C Capell, Golnaz Vahedi, Simone Sidoli, Roddy S O'Connor, Will Bailis, Nathaniel W Snyder, Kathryn E Wellen.
      Tissue microenvironments differ widely in nutrient composition; yet how local nutrient conditions shape epigenetic programs that direct immune cell fate is poorly understood. We identify histone lysine propionylation (Kpr) as a chromatin mechanism linking nutrient availability to T cell fate decisions. Proteomic analysis reveals that Kpr is broadly reduced in exhausted T cells. H3K18pr is enriched at stemness-associated loci in effector T cells and depleted upon exhaustion. Isoleucine and propionate supply propionyl-CoA in T cells, and restricted nutrient availability within the tumor microenvironment limits histone Kpr, promoting T cell exhaustion. Disrupting isoleucine catabolism in T cells further suppresses Kpr, without altering histone acetylation, and impairs T cell function and antitumor immunity in a manner rescued by propionate. Dietary supplementation of isoleucine and propionate increases Kpr in tumor infiltrating lymphocytes, limits exhaustion, and improves tumor control. These findings establish a microenvironment-chromatin axis crucial for antitumor immunity and amenable to nutritional intervention.
    DOI:  https://doi.org/10.64898/2026.10.01.756002
  4. Sci Adv. 2026 Oct 30. 12(44): eaeg0361
    Glucose restriction induced by intermittent fasting promotes alternative metabolic fluxes leading to memory CD8+ T cell development.
    Da-Jeong Park, Young-Jun Ju, Young Jin Pyung, Cheol Gyun Kim, Narae Kim, MinJi Lim, Hyungseok Seo, Seung Hyun Han, Jae-Ho Cho, Cheol-Heui Yun.
      Dietary restrictions are increasingly recognized as modulators of immune cell function. However, how they shape CD8+ T cell fate decisions remains incompletely understood. Here, we investigated the impact of intermittent fasting (IF) on differentiation of heterogeneous effector T cell subsets and the formation of a long-lived homeostatic memory pool. We found that IF skewed CD8+ T cell differentiation toward memory precursor effector cells (MPECs) and enhanced the central memory CD8+ T cell development and functions. Mechanistically, glucose restriction induced by IF promotes alternative metabolic fluxes leading to fatty acid oxidation. This metabolic shift enhanced mitochondrial fitness and supported MPEC differentiation via metabolic-epigenetic cross-talk, culminating in durable and functionally robust memory CD8+ T cell responses. Applying this strategy in adoptive transfer therapy, intratumoral defects could be circumvented by imprinting a memory phenotype under IF-mimicking conditions, resulting in improved and long-lasting antitumor activity. Collectively, these findings underscore the importance of IF in orchestrating metabolic-epigenetic cross-talk to enhance memory formation and antitumor immunity.
    DOI:  https://doi.org/10.1126/sciadv.aeg0361
  5. Acta Naturae. 2026 Jul-Sep;18(3):18(3): 4-18
    From Dysfunction to Differentiation: A New Paradigm of T Cell Exhaustion.
    V M Stepanova, A S Logvinov, E A Emelyanov, N A Katin, Yu P Rubtsov.
      CD8+ T cell exhaustion is the loss of certain functions typical of cytotoxic lymphocytes. CD8+ cytotoxic T cells originate from naive CD8+ T cells upon antigen exposure. Chronic or excessive antigen exposure during certain infections and cancers triggers inhibitory mechanisms that lead to functional exhaustion - a loss of the ability to secrete IFN-γ and other cytokines, as well as to produce granzyme- and perforin-containing lytic granules in response to stimulation. Functional exhaustion also affects CD4+ helper T cells, which further reduces CD8+ T cell cytotoxicity. This leads to the loss of the CD8+ T cell's ability to kill target cells, which negatively impacts immunity and reduces the efficacy of therapeutic T cells. Currently, T cell exhaustion is considered as a multistage, partially reversible differentiation program. Heterogeneous subsets of stem-like progenitor exhausted T cells (Tex-prog) and terminally exhausted T cells (Tex-term) have been identified. These cells differ in their degrees of dysfunction and, thus, in their potential to restore lost functions. The transcriptional exhaustion program is controlled by key transcription factors, such as TCF1, TOX, T-bet, EOMES, BATF, IRF4, etc. Understanding the dynamic changes taking place in the transcriptional profile and cellular phenotype is critical for effective immunotherapy, in particular in immune checkpoint blockade (ICB) and CAR-T cell therapy, because its success depends entirely on the T cell state. In this review, we discuss current concepts on the molecular and cellular mechanisms of T cell exhaustion, various exhaustion-associated phenotypic and functional changes, and opportunities for preventing T cell exhaustion to optimize anti-tumor immunotherapy strategies.
    Keywords:  CD8+ T cells; T cells; cellular immunotherapy; functional exhaustion; immune checkpoint blockade; negative co-stimulation; transcription factors
    DOI:  https://doi.org/10.32607/actanaturae.27873
  6. Cancer Discov. 2026 Oct 26.
    hnRNPA2B1 sustains antitumor T cell immunity and enhances cancer immunotherapy through IDR-dependent stabilization of chromatin-regulatory transcripts.
    Shi Liu, Wenyan Gao, Menghan Hu, Lingyun Long, Hongyan Chen, Yun Zhang, Xuetao Cao, Zhihua Liu.
      T cell exhaustion within the tumor microenvironment poses a major barrier to effective cancer immunotherapy, yet the epigenetic mechanisms that preserve functional states of tumor-infiltrating T cells remain incompletely understood. Here, using an in vivo CRISPR screen, we identify heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1) as a regulator of CD8+ T cell fitness. Transcriptomic analyses of cancer patient cohorts reveal that hnRNPA2B1 is preferentially enriched in a proliferative, intermediate exhausted T cell subset associated with favorable clinical outcomes. Genetic ablation of hnRNPA2B1 in CD8+ T cells accelerates terminal exhaustion, impairs antitumor immunity, and diminishes responsiveness to immune checkpoint blockade. Mechanistically, hnRNPA2B1 forms nuclear puncta and stabilizes RNAs involved in chromatin organization, thereby maintaining chromatin accessibility that restrains exhaustion-associated programs while preserving proliferative and cytotoxic potential. Together, these findings establish hnRNPA2B1 as an RNA-mediated epigenetic regulator sustaining functional exhausted T cell states in tumors.
    DOI:  https://doi.org/10.1158/2159-8290.CD-26-0255
  7. Trends Endocrinol Metab. 2026 Oct 27. pii: S1043-2760(26)00274-2. [Epub ahead of print]
    The fate of cysteine's sulfur in CD8+ T cell function.
    Beth Kelly, Erika L Pearce.
      CD8+ T cells modulate their metabolism to support activation, proliferation, and effector function. The sulfur-containing amino acid cysteine is essential for these processes, but beyond its role in protein synthesis, cysteine is metabolized into multiple products that differentially regulate T cell immunity. Here, we review recent advances in understanding how intracellular cysteine routing controls CD8+ T cell function. Cysteine-derived glutathione, iron-sulfur clusters, coenzyme A, hydrogen sulfide, and taurine each have distinct effects on T cell activation, mitochondrial metabolism, and antitumor immunity. Additionally, cysteine-dependent post-translational modifications-including sulfenylation and persulfidation-modulate signaling and gene expression. Understanding how cells balance competing cysteine fates may reveal new therapeutic strategies to enhance T cell responses in cancer and other diseases.
    Keywords:  CD8(+) T cell; Fe–S cluster; cysteine; glutathione; immunometabolism; sulfur
    DOI:  https://doi.org/10.1016/j.tem.2026.10.002
  8. Adv Mater. 2026 Oct 26. pii: e75515. [Epub ahead of print]
    Time-Encoded Ligand Presentation via a Magnetically Actuated Hydrogel Mitigates T Cell Exhaustion.
    Xuemei Wang, Runyao Wang, Guangli Xiang, Xueyou Zhang, Luyang Wang, Wai Ki Wong, Yingrui Deng, Yongkang Yang, Jiwon Oh, Xian Xie, Zhinan Yang, Nathanael Chun Him Lai, Bohan Yin, Kunyu Zhang, Liming Bian, Siu Hong Dexter Wong.
      Adoptive T cell therapy (ACT) requires ex vivo expansion of tumor-reactive CD8+ T cells, yet prolonged antigenic stimulation frequently induces exhaustion, limiting persistence and therapeutic efficacy. Here, we present a magnetically actuated, extracellular matrix-mimetic hydrogel that enables reversible control of T cell receptor (TCR) stimulation timing. By embedding αCD3ε/αCD28-functionalized magnetic nanoparticles within a soft hyaluronic acid matrix, external magnetic fields dynamically expose or conceal stimulatory ligands, allowing programmable alternation between activation and rest. Continuous ligand presentation sustains TCR signaling and drives inhibitory receptor expression and functional exhaustion. In contrast, alternating activation-rest cycles periodically attenuate proximal TCR signaling, reduce exhaustion-associated marker expression, and bias differentiation toward central memory-like states while preserving cytokine production and recall capacity. T cells expanded under intermittent stimulation exhibit enhanced antigen-specific cytotoxicity, reduced dependence on PD-1 blockade, and superior tumor control in vivo, together with increased CD8+ T cell abundance across analyzed tissues. These results identify temporal control of mechanochemical signaling as a materials-encoded regulator of T cell fate and provide a non-genetic strategy for generating functionally competent T cell products with reduced exhaustion-associated dysfunction and improved antitumor activity.
    Keywords:  T cell exhaustion; adoptive cell therapy; dynamic ligand presentation; immuno‐materials engineering; magnetically actuated hydrogel; time‐encoded signaling
    DOI:  https://doi.org/10.1002/adma.75515
  9. Eur J Immunol. 2026 Oct;pii: e70286. [Epub ahead of print]56(10):
    Beyond Exhaustion: The RNA Regulatory Layer of Tissue-Instructed T Cell Dysfunction.
    Francesco Andreata, Federica Marasca, Beatrice Bodega, Matteo Iannacone.
      CD8+ T cell exhaustion is a differentiation program driven by persistent antigen stimulation and stabilized through multiple regulatory layers, including transcription factor networks and chromatin. Beyond these established frameworks, an RNA regulatory layer, encompassing noncoding RNAs, RNA-binding proteins, alternative splicing isoforms, and epitranscriptomic modifications, is emerging as a further determinant of exhausted T cell identity. Retrotransposon-derived transcripts remain largely underexplored in this context, with the exception of LINE1-containing transcripts, which are causally linked to exhaustion and directly therapeutically addressable. Yet, whether this RNA layer is a generalizable feature of exhaustion or is instead instructed by the tissue in which antigen priming occurs remains unknown. Most of the current understanding derives from settings in which naïve CD8+ T cells are primed by professional antigen-presenting cells in secondary lymphoid organs. In the liver, however, hepatocytes can prime naïve CD8+ T cells directly, generating a hypofunctional state that is transcriptionally and pharmacologically distinct from canonical exhaustion, refractory to checkpoint blockade yet reversible by 4-1BB agonism. We propose that the RNA regulatory layer is a plausible substrate through which tissue-derived signals are encoded, and that the liver offers a powerful model to define and therapeutically target tissue-instructed T cell dysfunction.
    Keywords:  CD8+ T cell exhaustion; LINE1 retrotransposons; Liver immunology; RNA therapeutics; Regulatory RNAs
    DOI:  https://doi.org/10.1002/eji.70286
  10. Biomedicines. 2026 Oct 15. pii: 2347. [Epub ahead of print]14(10):
    Deoxycorticosterone Reshapes CD8+ T Cell State and Effector Function Through Distinct Metabolic Signaling Programs.
    Tao Li, Anqi Chen, Siqi Zhou, Gang Xue.
      Background/Objectives: Whether individual endogenous corticosteroids exert distinct immunoregulatory effects on CD8+ T cells remains poorly understood. We investigated how deoxycorticosterone (DOC) affects CD8+ T cell state and function. Methods: Primary mouse CD8+ T cells were activated with anti-CD3/CD28 and IL-2 in the presence or absence of DOC. Flow cytometry was used to assess exhaustion-associated markers and effector function, and pharmacological perturbations were used to examine the involvement of AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), and protein kinase B (AKT) signaling. Results: DOC promoted an exhaustion-associated phenotype characterized by increased frequencies of PD-1+LAG-3+ and PD-1+TIM-3+ cells and elevated TOX expression. DOC concurrently impaired effector function, reducing IFN-γ/TNF co-production, granzyme B expression, and IL-2 production. Pharmacological inhibition of AMPK or activation of mTOR partially attenuated exhaustion-associated features induced by DOC, whereas AKT activation partially restored effector function. Conclusions: DOC directly reshapes CD8+ T cell state and function in vitro, with exhaustion-associated and effector responses exhibiting distinct pharmacological signaling dependencies. These findings identify DOC as a previously underappreciated endogenous corticosteroid capable of modulating CD8+ T cell biology.
    Keywords:  CD8+ T cells; T cell exhaustion; deoxycorticosterone; immunometabolism; metabolic signaling
    DOI:  https://doi.org/10.3390/biomedicines14102347
  11. bioRxiv. 2026 Oct 07. pii: 2026.10.06.756889. [Epub ahead of print]
    One-carbon metabolism sustains effector T cell function through cell-surface glycosylation.
    Peng Wang, Amy Yu, Mohammed Mutaher, Almut S Eisele, Sarah Mouche, Kaitlyn Hung, Reece C Larson, Madeline Gish, Margaret Zimmer, Jeanette R Brook, Miriam McNerney, Lea Hammer, Arjun Garg, Efrat Ozeri, Alan Y L Wong, Boryana Petrova, Michal Weitman, Ramon C Sun, Jerome Tamburini, Mathias Wenes, Marc Schwartz, Nir Hacohen, Naama Kanarek.
      Folate is an essential driver of one-carbon metabolism. The cellular consequences of its deprivation in CD8 + T cell and impact on anti-tumor function are unknown. Single cell RNA-seq analysis of primary central nervous system lymphoma (PCNSL) patients' tumor samples revealed exhaustion in T cells with high folate metabolism gene expression signature. Functional genomics, metabolite profiling, and glycomics identified disrupted cell surface glycosylation as a major consequence of folate deprivation in CD8 + T cells. Mechanistically, folate deprivation reduced nucleotide sugar levels, perturbed glycosylation, and triggered the apoptotic unfolded protein response. Overexpressing folate transporters in adoptively transferred CD8 + T cells increased intratumoral T cell numbers and reduced exhaustion. Therefore, our data draw a mechanistic line between one-carbon metabolism, cell-surface glycosylation, and anti-tumor T cell function, and support a hypothesis that increased folate uptake can enhance CD8 + T cell function including ex vivo and in vivo CAR-T cells.
    Highlights: Although folate metabolism genes are highly expressed in both proliferating tumor and CD8 + T cells from primary central nervous system lymphoma patients, the T cells are exhausted while the tumor cells thrive Folate is depleted in the TME of MC38-OVA and B16-OVA tumors Folate deprivation impairs function and proliferation of CD8 + T cells Folate is essential for nucleotide sugar metabolism, and its depletion results in perturbation of cell surface glycosylationGenetic engineering to increase folate uptake by T cells increases intratumoral T cell numbers and reduces exhaustion.
    DOI:  https://doi.org/10.64898/2026.10.06.756889
  12. bioRxiv. 2026 Sep 05. pii: 2026.09.01.748651. [Epub ahead of print]
    The Notch signaling pathway is a master regulator of CD8+ T cell exhaustion and differentiation during chronic infection.
    Dave Maurice De Sousa, Salix Boulet, Frédéric Duval, Eric Perkey, Jean-François Daudelin, Laure Le Corre, Marie-Ève Lebel, Alain Lamarre, Freddy Radtke, Burkhard Ludewig, Chris Siebel, Ivan Maillard, Nathalie Labrecque.
      During chronic infection, the persistence of antigen and inflammation leads to the differentiation of CD8+ T cells into an exhausted state characterised by expression of inhibitory receptors (IRs) and the progressive loss of T cell functions. Among the different subsets of exhausted CD8+ T (Tex) cells, Tex progenitors expressing SLAMF6 and the transcription factor TCF-1 (TCF-1+) give rise to Tex effector-like cells expressing CX3CR1 and Tex terminal cells expressing CD101. PD-1/PD-L1 blockade acts on TCF-1+ Tex progenitor cells and promotes their differentiation into Tex effector-like cells. The molecular events controlling CD8+ Tex cell differentiation are still poorly defined. As Notch signaling may be sustained during chronic infection by persistent TCR stimulation and inflammation, we tested whether Notch signaling influences CD8+ T cell exhaustion. Using mice lacking (N1N2Δ/Δ) or not (N1N2fl/fl) Notch1/2 expression only in mature CD8+ T cells, we showed that the absence of Notch signal causes severe CD8+ T cell exhaustion during chronic LCMV infection. N1N2Δ/Δ Tex cells express higher levels of IRs and are less functional when compared to their wild-typee counterpart. In the absence of N1N2 receptors, Tex progenitor and Tex terminal cells accumulate and Tex cells cannot be reinvigorated by PD-1/PD-L1 blockade. We further demonstrated that Notch signaling is essential to promote the differentiation of Tex progenitors into Tex effector-like cells. Moreover, Notch signals, provided by stromal cells expressing the ligands Delta-like 1 and 4, are necessary during all stages of the infection to prevent severe exhaustion. Single-nucleus RNA and ATAC multiome profiling identifies Notch signaling as a critical role on effector transcriptional programming in exhausted CD8 T cells. Loss of Notch signaling impairs transcriptional program associated with migration and perception of CD4+ T cell help. Together, these alterations drive the differentiation of Tex progenitor cells toward a terminally exhausted Tex fate.
    DOI:  https://doi.org/10.64898/2026.09.01.748651
  13. Front Immunol. 2026 ;17 1961063
    T-cell metabolic reprogramming in systemic lupus erythematosus: linking intracellular metabolism to effector differentiation and senescent-like/exhausted-like states.
    Yi Zou, Zhichu Ren, Yuki Kudo, Michihito Kono.
      Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation and multiorgan inflammation. T-cell metabolic reprogramming has recently emerged as an active area of investigation in the pathogenesis of SLE. This metabolic reprogramming, which involves glycolysis, mitochondrial oxidative phosphorylation, glutamine metabolism, and lipid metabolism, is associated not only with functional alterations in SLE T cells but also with changes in their differentiation and proliferation, potentially contributing to disease pathogenesis and progression. Moreover, metabolic alterations, including mitochondrial dysfunction and reactive oxygen species accumulation, in the context of persistent T-cell activation may contribute to phenotypic transitions toward senescent-like or exhausted-like states. These two partially overlapping but biologically distinct cellular phenotypes may represent divergent cellular responses to chronic inflammatory stimulation. Rather than representing mutually exclusive states or a simple loss of function, both may contribute to the perpetuation of chronic inflammation, immune imbalance and disease activity. This review summarizes recent advances in T-cell metabolic reprogramming in SLE and its potential relationship to senescent-like and exhausted-like T-cell states.
    Keywords:  exhausted-like T cells; immunometabolism; metabolic reprogramming; senescent-like T cells; systemic lupus erythematosus
    DOI:  https://doi.org/10.3389/fimmu.2026.1961063
  14. Front Immunol. 2026 ;17 1910235
    p53 activation via pharmacologic MDM2 inhibition constrains exhaustion and enhances antitumor function of human CD8+ T cells.
    Alexandra Boix de Jesus, Hy B Dao, Anthony Imani, Gabriel A Rodriguez, Michael S Shehata, Rachana R Chandran, Stuart A Fine, Sin Y Lim, Michelle To, Serena Y Lofftus, Nicolas Pedroncelli, Fritz C Eilber, Brigitte N Gomperts, Tyler R McCaw, Cristina Puig-Saus, Joseph G Crompton.
      Adoptive T-cell therapies using chimeric antigen receptors (CARs) or engineered T-cell receptors (TCRs) have transformed cancer treatment but remain limited by poor persistence and progressive T-cell exhaustion. Manufacturing strategies that promote memory T-cell formation may improve therapeutic durability. Here we investigated whether transient pharmacologic activation of the p53 pathway influences the differentiation and function of human CD8+ T cells. p53 expression was minimal in quiescent naïve CD8+ T cells but was rapidly induced following T-cell receptor activation. Pharmacologic inhibition of the p53 negative regulator MDM2 increased p53 protein levels and promoted expansion of central memory and stem-like memory T-cell subsets during clonal proliferation. Treated cells displayed enhanced mitochondrial fitness, increased polyfunctional cytokine production, and transcriptional programs consistent with memory differentiation and reduced exhaustion. Importantly, TCR-engineered CD8+ T cells generated in the presence of the MDM2 inhibitor Navtemadlin demonstrated superior tumor-cell killing in vitro compared with conventionally manufactured cells. These findings identify transient p53 activation as a pharmacologic strategy to enhance memory programming during T-cell manufacturing and suggest a clinically feasible approach to improve the efficacy of adoptive T-cell immunotherapies.
    Keywords:  CD8; T-cell memory; exhaustion; immunotherapy; metabolic fitness; p53
    DOI:  https://doi.org/10.3389/fimmu.2026.1910235
  15. Cell Rep. 2026 Oct 26. pii: S2211-1247(26)01235-0. [Epub ahead of print]45(11): 118156
    Single-cell multi-omics reveals archetypal regulatory programs shared across T cell subsets.
    Sarah K Walker, Joris van der Veeken, Alexander Y Rudensky, Yuri Pritykin.
      T cells differentiate into functionally distinct subsets in response to pathogens, yet essential immune functions such as self-renewal, expansion, cytokine production, and cytotoxicity are common to multiple subsets and therefore must be programmed via shared regulatory mechanisms. To uncover these "archetypal" epigenomic programs, we integrated a single-cell multiomic (scATAC+RNA-seq) dataset of CD4 and CD8 T cells responding to acute and chronic viral infection with a comprehensive bulk ATAC-seq compendium. Our analysis reveals a modular architecture governing T cell identity, implicating distinct transcription factors in reusing regulatory programs across subsets and lineages. Notably, translationally important progenitor CD8 T cells, critical for sustained immunity and present in both acute and chronic infection, exhibit a composite regulatory state, combining a CD8 exhaustion program with a follicular helper CD4 T cell program. In sum, this resource and generalizable computational framework will aid the mechanistic dissection of adaptive immunity and immunotherapy design.
    Keywords:  CP: genomics; CP: immunology; LCMV; T cell exhaustion; Tfh; Tpex; follicular helper T cells; gene regulation; progenitor exhausted CD8 T cells; scATAC-seq; scRNA-seq; single-cell multi-omics
    DOI:  https://doi.org/10.1016/j.celrep.2026.118156
  16. Int J Mol Sci. 2026 Oct 15. pii: 9134. [Epub ahead of print]27(20):
    Metabolic Dysfunction and T-Cell Exhaustion in Colorectal Cancer: Mechanisms, Microenvironment Remodeling, and Therapeutic Opportunities.
    Jieun Jeon, Hye Suk Baek, Kibeom Park, Mee-Na Park, Na Hyeon Heo, Sohyeon Cheon, Gahyeon Kim, Shin Kim.
      Colorectal cancer (CRC) remains a major cause of cancer-related morbidity and mortality worldwide. Metabolic disorders such as obesity, diabetes mellitus, dyslipidemia, and metabolic syndrome are associated with CRC risk. Metabolic abnormalities may contribute to colorectal tumorigenesis and reshape the tumor immune microenvironment, which in turn influence immune dysfunction and therapeutic resistance. Exhausted CD8+ T cells exhibit impaired effector function, sustained inhibitory receptor expression, and transcriptional and epigenetic reprogramming. Metabolic stressors within the CRC microenvironment may modulate T-cell function and exhaustion-associated states. Additionally, other immune populations (natural killer cells, macrophages, myeloid-derived suppressor cells, dendritic cells, and regulatory T cells) may develop distinct dysfunctional or immunosuppressive states. Recent single-cell and spatial studies have indicated the heterogeneity of these immunometabolic interactions in CRC. This review examines the interactions of the systemic and tumor-associated metabolic alterations with T-cell exhaustion and other forms of immune dysfunction in CRC. We discuss the influence of glucose, lipid, amino acid, and mitochondrial metabolism, hypoxia, microbiota-derived metabolites, and chronic inflammation in shaping tumor-immune interactions. Finally, we reviewed therapeutic strategies targeting immunometabolic pathways and their potential integration with immune checkpoint blockade. Overall, understanding these interactions may help identify immunometabolic vulnerabilities for informing precise therapeutic strategies for CRC.
    Keywords:  T-cell exhaustion; colorectal cancer; diabetes mellitus; immune checkpoint blockade; immunometabolism; metabolic dysfunction; microbiota; obesity; therapeutic resistance; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms27209134
  17. Immunol Invest. 2026 Oct 28. 1-25
    Neutrophil-Derived Arg1 Impairs CD8+ T Cell Activity in Sepsis Through mTOR-Mediated Mitochondrial Dysfunction.
    Qiulin Peng, Liuqing Yang.
       BACKGROUND: This research aimed to elucidate the contribution of Arginase 1 (Arg1) to pediatric sepsis progression, specifically impacting the effector functions of CD8+ T lymphocytes.
    METHODS: Arg1 expression was assessed in venous blood from pediatric sepsis patients (n = 21) and healthy volunteers (n = 21). Pharmacological inhibition of Arg1 was achieved using Nor-NOHA in both sepsis patients-derived neutrophils and LPS-stimulated healthy neutrophils, followed by co-culture with CD8+ T cells. Sepsis-derived neutrophils were also treated with hArg1 monoclonal antibody (mAb). CD8+ T cell viability, exhaustion markers (PD-1/TIM-3), mitochondrial membrane potential, ATP production, autophagy, and inflammatory cytokine secretion were systematically evaluated.
    RESULTS: Arg1 expression was markedly upregulated in sepsis patients correlated positively with neutrophil counts but negatively with CD8+ T cell numbers and mitochondrial function. Strikingly, CD8+ T cells from Arg1-high patients exhibited increased PD-1+TIM-3+ double-positive populations. Both Nor-NOHA-mediated Arg1 inhibition and hArg1-mAb neutralization significantly restored CD8+ T cell mitochondrial membrane potential (MMP), ATP production, and effector cytokine secretion, while concurrently reducing PD-1/TIM-3 expression.
    CONCLUSION: Our findings indicate that overexpression of Arg1 derived from neutrophils leads to a highly inflammatory response suggesting that Arg1 is a potential prognostic biomarker and therapeutic target in pediatric sepsis.
    Keywords:  Arg1; CD8+ T cell; mitochondrial impairment; neutrophil; sepsis
    DOI:  https://doi.org/10.1080/08820139.2026.2750409
  18. Clin Exp Immunol. 2026 Oct 27. pii: uxag066. [Epub ahead of print]
    T cell metabolic ageing as a factor for therapeutic research.
    Ellen King, Bahar Zinali Sohanaki, Anna Schurich.
      Ageing is an important determinant of immune function across the lifespan, yet it remains underappreciated in the design and interpretation of much basic T cell research. As the immune system ages, T cell responses become less diverse, less efficient, and less adaptable, with consequences for infection control, vaccine responsiveness, cancer immunosurveillance, and the performance of T cell-based immunotherapies. This issue is particularly acute because many fundamental studies still rely on T cells from, mostly, healthy young donors. These controls are indispensable, but the field has built much of its pre-clinical logic on immune systems that are younger, fitter, and biologically distinct from the patients for whom T cell therapies are intended. We argue that this mismatch between experimental systems and clinical reality could be overcome by considering age as a routine variable from the start.
    Keywords:  T cell; ageing; metabolism
    DOI:  https://doi.org/10.1093/cei/uxag066
  19. Int Immunol. 2026 Oct 30. pii: dxag057. [Epub ahead of print]
    Spermidine disrupts mitochondrial respiration and redox homeostasis in aged CD44+ CD49d- CD8+ T cells.
    Jun Wang, Yu Wang, Koki Ichimaru, Maharani Aprilia, Yasuharu Haku, Jiaxin Gu, Mai Kiyono, Keiko Yurimoto, Tomonori Yaguchi, Tasuku Honjo, Koji Kitaoka, Kenji Chamoto.
      Spermidine (SPD) is a polyamine metabolite with anti-aging and immunomodulatory properties. We previously reported that SPD enhances mitochondrial respiration in CD44- CD8+ naïve T cells through the upregulation of fatty acid oxidation (FAO). However, the effects of SPD on CD44+ CD8+ effector T cells remain unknown. We found that SPD suppressed mitochondrial oxygen consumption rate (OCR) in CD44+ CD8+ T cells from aged mice, in contrast to its effects on those from young mice. This FAO-dependent reduction in respiration was associated with mitochondrial oxidative stress and accompanied by reduced IFN-γ production and proliferative capacity. Notably, within the aged CD44+ CD8+ T cell compartment, senescence-like CD44+ CD49d- subset (CD49d- cells)-predominantly accumulated with age-exhibited a marked decrease in OCR following SPD treatment, whereas CD44+ CD49d+ CD8+ T cells (CD49d+ cells) were unaffected. In CD49d- cells, SPD treatment disrupted redox balance as evidenced by reduced intracellular reduced-thiol levels with unchanged mitochondrial reactive oxygen species (ROS) levels, suggesting consumption of antioxidant reserves. SPD also induced structural remodeling of mitochondria in CD49d- cells, characterized by a shift toward shorter, more fragmented mitochondria with wider cristae spacing than in CD49d+ cells. In summary, our findings reveal that SPD paradoxically compromises mitochondrial respiration in a specific subset of aged CD8+ T cells by perturbing fatty acid metabolism and redox homeostasis.
    Keywords:  fatty acid oxidation; mitochondrial damage; oxidative stress; polyamine
    DOI:  https://doi.org/10.1093/intimm/dxag057
  20. Biomolecules. 2026 Oct 13. pii: 1487. [Epub ahead of print]16(10):
    Immunosenescence in Aging and Cancer: Molecular Mechanisms, Tumor Microenvironment Remodeling, and Therapeutic Implications.
    Yusra Zarlashat, Syed Salman Shah, Seerat-Uz-Zahra, Rosa Di Lorenzo, Anna Picca.
      Immunosenescence is the decline in immune function with age, which influences cancer progression and treatment outcomes. This process arises from multiple, interconnected molecular and cellular alterations. Among these, mitochondrial dysfunction in aged immune cells may contribute to impaired immune function through altered metabolism, redox imbalance, and inflammatory signaling. This review discusses mitochondrial alterations alongside other age-related mechanisms that shape immune cell function and may promote cancer development. We examine how DNA damage, telomere shortening, epigenetic changes, altered proteostasis, and mitochondrial dysfunction contribute to immune aging and potentially compromise antitumor immunity. The aged tumor microenvironment is characterized by increased immunosuppressive cell populations, persistent inflammatory signaling, and metabolic alterations that can influence tumor development and therapeutic responses. We also examine how aging affects response to current cancer immunotherapies. While some treatments show comparable efficacy in older and younger patients, others may be less effective in the context of age-related immune dysfunction. Older patients may also experience distinct toxicity profiles that require careful clinical management. Understanding how mitochondrial alterations interact with other mechanisms of aging to shape immunosenescence may help identify therapeutic strategies for cancer in older adults. Future approaches may combine interventions targeting mitochondrial fitness, chronic inflammation, and cellular senescence. However, clinical studies specifically designed to include older populations are needed to establish the relevance of these mechanisms in cancer and to guide age-specific therapeutic strategies.
    Keywords:  Immunosenescence; aging immune system; cancer immunotherapy; chronic inflammation; immune checkpoint inhibitors; inflammaging; mitochondrial dysfunction; mitochondrial quality control; tumor microenvironment
    DOI:  https://doi.org/10.3390/biom16101487
  21. Res Sq. 2026 Sep 04. pii: rs.3.rs-10692330. [Epub ahead of print]
    Interferons and STAT1 dynamically modulate integrated stress response outcomes in CD8 T cells.
    Rachael Philips, Kang Yu, Yi-Chu Liao, SeolKyoung Jung, Kan Jiang, Yuka Kanno, Davide Randazzo, Scott Oakes, John O'Shea.
      Type I interferons (IFN-I) drive both protective and pathological CD8 T cell responses. Patients with activating STAT1 mutations exhibit enhanced IFN responses with T cell dysfunction and autoimmunity; however, mechanisms underlying excess versus impaired response remain unclear. We used mouse models expressing a STAT1 mutation (Stat1-T385M) ubiquitously or T-cell selectively to dissect T cell-intrinsic versus cell-extrinsic actions of activating STAT1. Global Stat1-T385M expression had increased lethality upon acute viral infection with CD8 T cell dysfunction marked by stress response activation rather than classical exhaustion. This dysfunction was extrinsic, as T-cell-restricted Stat1-T385M preserved expansion, cytokine production, and checkpoint receptor expression. However, intrinsic Stat1-T385M reshaped differentiation by suppressing T-bet and effector programs while upregulating a stress signature seen in memory lymphocytes. The extrinsic-intrinsic switch depended on IFN-I magnitude, with exaggerated levels triggering a pro-apoptotic stress response. Therefore, STAT1 works as a rheostat balancing CD8 differentiation and stress, as a basis for interferonopathies.
    DOI:  https://doi.org/10.21203/rs.3.rs-10692330/v1
  22. bioRxiv. 2026 Sep 05. pii: 2026.09.02.747634. [Epub ahead of print]
    Metabolically Activated Proteostasis Regulators Reduce Differentiation of CD4+ TH17 Cells.
    Priyadarshini Chatterjee, Keishla Sánchez Ortiz, Stanislav Dikiy, Michael J Bollong, Jessica E Thaxton, Alejandra Mendoza, R Luke Wiseman.
      The differentiation of naïve CD4+ T cells into effector T cell subsets such as TH1, TH2, TH17 and TREG cells is governed by tightly coordinated activation programmes dependent on T cell receptor (TCR) engagement, co-stimulation, and cytokine signalling. This differentiation process involves regulation of stress-responsive signalling pathways such as the unfolded protein response (UPR) and the oxidative stress response (OSR) to adapt to the physiologic demands specific to distinct T cell subset functions. This suggests that pharmacologically targeting stress-responsive pathways offers a unique opportunity to selectively remodel the differentiation of these different T cell subsets. We previously identified compound AA147 as a metabolically activated proteostasis regulator that can induce both the ATF6 signalling arm of the UPR and, in certain cell types, the NRF2-regulated arm of the OSR.(Paxman et al., 2018; Plate et al., 2016) Here, we show that treatment with AA147 selectively reduces differentiation of pro-inflammatory TH17 cells by promoting degradation of the lineage-specifying transcription factor RORγt, without impacting the transcription factors of other CD4+ T cell subsets. We find that AA147-dependent reduction in TH17 differentiation is independent of ATF6 activation but involves NRF2 activation and reductions in intracellular reactive oxygen species (ROS). Apart from RORγt, we further show that AA147 decreases expression of the TCR-responsive factor IRF4, thus suppressing production of select effector cytokines across effector T cells, revealing additional ways in which this compound reshapes the activities of these essential T cell subsets. Our results demonstrate the potential for metabolically activated proteostasis regulators such as AA147 to selectively reshape TH17 cell identity while broadly dampening effector cytokine responses across effector T cell subsets.
    Keywords:  NRF2; TH17 differentiation; oxidative stress response; proteostasis regulator
    DOI:  https://doi.org/10.64898/2026.09.02.747634
  23. Clin Exp Immunol. 2026 Oct 30. pii: uxag071. [Epub ahead of print]
    Targeting Immune Cell Metabolism for Tolerance.
    Nicholas Jones.
      
    Keywords:  Autoimmunity; immunometabolism; metabolism; mitochondria
    DOI:  https://doi.org/10.1093/cei/uxag071
  24. Front Pediatr. 2026 ;14 1923893
    Hypoxic conditioning of neuroblastoma cells promotes CD8+ T-cell dysfunction through the HIF-1α/PD-L1 axis.
    Yujin Chao, Guili Zheng.
       Objective: To investigate whether hypoxic conditioning of neuroblastoma (NB) cells induces CD8+ T cell dysfunction/exhaustion-like phenotype via the HIF-1α/PD-L1 axis and whether targeting this axis reverses immune suppression.
    Methods: Human NB cell lines SK-N-SH, SK-N-BE(2), and SK-N-AS were exposed to 1% O₂ hypoxia. HIF-1α and PD-L1 expression were assessed by Western blot, qRT-PCR, and flow cytometry. ChIP-qPCR and dual-luciferase assays were used to verify HIF-1α binding and transcriptional activation of the PD-L1 promoter. SK-N-SH cells pre-conditioned under normoxia or hypoxia were co-cultured with primary human CD8+ T cells. CD8+ T cell dysfunction/exhaustion-like phenotype (PD-1+TIM-3+), apoptosis, IFN-γ, Granzyme B, CD107a, and specific cytotoxicity were evaluated. HIF-1α siRNA, YC-1, and PD-L1 neutralizing antibody were applied. The direct effect of YC-1 on T cells was also assessed.
    Results: Hypoxia increased HIF-1α and PD-L1 expression in a time-dependent manner and also upregulated PD-L1 in additional NB cell lines. ChIP-qPCR and dual-luciferase assays confirmed direct HIF-1α binding to the HRE (5'-AGGTGC-3') and transcriptional activation. PD-L1 elevation declined after reoxygenation. Hypoxia-preconditioned NB cells increased PD-1+TIM-3+ CD8+ T cells (5.49%-32.24%) and apoptosis (10.61%-26.89%), while reducing IFN-γ +, Granzyme B+, CD107a+ cells and specific cytotoxicity (79.94%-38.40%). HIF-1α knockdown or PD-L1 blockade alleviated these effects. YC-1 at 25 μM did not significantly affect T cell viability or IFN-γ secretion.
    Conclusion: Hypoxic conditioning of NB cells stabilizes HIF-1α, enhances its binding to the PD-L1 promoter HRE, upregulates PD-L1, and induces CD8+ T cell dysfunction/exhaustion-like phenotype and impaired antitumor function. Targeting HIF-1α or PD-L1 partially restores T cell function in this co-culture model. The hypoxia-driven HIF-1α/PD-L1 axis contributes to immune suppression in NB and may be a potential therapeutic target.
    Keywords:  HIF-1α; PD-l1; T cell dysfunction; exhaustion-like phenotype; hypoxia; neuroblastoma
    DOI:  https://doi.org/10.3389/fped.2026.1923893
  25. Front Immunol. 2026 ;17 1905956
    Reconciling CD8 T cell subsets: GZMK+, cytotoxic, resident memory, exhausted, and other CD8 T cells in blood and tissue.
    Kaylee L Mickens, Anna Helena Jonsson.
      CD8 T cells represent a large portion of lymphocytes in blood as well as in inflamed tissues. Recent studies have shed new light on the populations present in tissues during health and disease, prompting a re-evaluation of the roles CD8 T cells can play in human pathophysiology. Inconsistent and overlapping CD8 T cell subset nomenclature and definitions present current challenges in the field and a barrier to interpreting the literature. In this review, we discuss CD8 T cell subsets in blood and tissues, including markers, phenotypes, and migration patterns. We also address intersections among these populations, including areas of ambiguity that warrant further research. To simplify the analysis of human RNA-seq datasets from sites of disease, we propose that stratifying cells by expression of granzyme B (GZMB) versus granzyme K (GZMK) provides a useful framework that emphasizes effector function phenotypes. We lastly summarize disease associations for granzyme B- and granzyme K-expressing CD8 T cell subsets.
    Keywords:  CD8 T cell; cytotoxic CD8 T cells; exhausted T cells (Tex); granzyme B; granzyme K; resident memory T (TRM) cells; tissue
    DOI:  https://doi.org/10.3389/fimmu.2026.1905956
  26. Cancer Res. 2026 Oct 27.
    SLC3A2 Drives an Immunosuppressive Metabolic Axis that Limits Oncolytic Virotherapy Efficacy.
    Weiwei Dai, Rihan Hai, Shasha Bian, Yan Dong, Bowen Yin, Yuling Chen, Xi Chen, Zhuoyang Fan, Yiheng Cai, Minfeng Shu.
      Oncolytic virotherapy is a promising cancer treatment that elicits antitumor immunity. However, the efficacy of virotherapy is often constrained by tumor-intrinsic immune suppression. To identify conserved virus-induced programs driving immune escape, we applied multi-omics and functional assays across multiple tumor and virus models, uncovering an SLC3A2-driven immunosuppressive metabolic barrier. In oncolytic herpes simplex virus (oHSV)-infected tumors, a biphasic immune trajectory emerged: early CD8+ T cell activation was followed by SLC3A2-mediated methionine and tryptophan uptake, driving T cell exhaustion. Mechanistically, oHSV upregulated SLC3A2 via the m6A-IGF2BP3 axis, while tumor-intrinsic tryptophan metabolism engaged the AHR/ARNT/ICP4 cascade to amplify viral replication and reinforce the immunosuppressive program. Importantly, dietary methionine supplementation disrupted the metabolic checkpoint, restored T cell effector function, and synergized with oHSV expressing anti-PD1 to enhance tumor control in humanized preclinical models. Notably, a parallel SLC3A2-centered metabolic-immunologic circuit operated in vesicular stomatitis virus (VSV) infection. Together, these findings delineate an actionable, conserved metabolic checkpoint and provide a framework for integrating metabolic modulation into cancer viroimmunotherapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-1659
  27. Nat Rev Immunol. 2026 Oct 27.
    An epigenetic regulator that promotes NK cell function.
    Juliana Lourenco, Arthur Mortha.
      
    DOI:  https://doi.org/10.1038/s41577-026-01370-7
  28. Cell Metab. 2026 Oct 28. pii: S1550-4131(26)00439-0. [Epub ahead of print]
    Arginine rewires eIF4F translation initiation to overcome fever-induced CAR T cell dysfunction.
    Taisuke Kondo, Makoto Ando, Josquin Moraly, Justyn DuSold, Abdallah Abdelmaksoud, Hannah W Song, Lakshmi Balagopalan, Dongya Jia, Laetitia Racine, Andy D Tran, Sooraj Achar, Serifat O Adebola, Pedro Gonzalez-Menendez, John Buckley, Anjali Chandroth, Alka Dwivedi, Nikolaos Svoronos, Angela Su, Christopher D Chien, Alexander D Clark, Xiyuan Zhang, Bonnie Yates, King Chan, Stephen D Fox, Xia Xu, Nicholas P Restifo, Neeraja Syed, Michael C Kelly, Michael Kruhlak, Yuki Kagoya, Rémy Bosselut, Jack F Shern, Thorkell Andresson, Valérie Dardalhon, Craig J Thomas, Steven L Highfill, Nirali N Shah, Grégoire Altan-Bonnet, Naomi Taylor.
      Chimeric antigen receptor (CAR) T cell therapy has revolutionized treatment of hematological malignancies, but cytokine release syndrome (CRS) remains a major toxicity. Fever-a hallmark of CRS-has been understudied as a modifier of therapeutic efficacy. In a retrospective cohort of patients with B cell acute lymphoblastic leukemia treated with CD22-directed CAR T cells (NCT02315612), sustained high-grade fever inversely correlated with clinical response. Mechanistically, experimental hyperthermia impaired proximal CAR signaling, reduced cytotoxicity, and compromised metabolic fitness through dysregulated arginine metabolism. Arginine supplementation restored CAR T cell function following hyperthermic stress and enhanced cytotoxicity under normothermic conditions. This effect required mTOR-dependent recruitment of the eIF4F translation-initiation complex and downstream c-MYC-driven metabolic reprogramming. Importantly, arginine enhanced good manufacturing practice (GMP)-manufactured CAR T cell function under normothermia, while oral supplementation improved in vivo efficacy. These findings identify metabolic control of translation as a fever-sensitive checkpoint and establish arginine supplementation as a tractable strategy to enhance CAR T cell efficacy.
    Keywords:  CD22; arginine; c-MYC; chimeric antigen receptor T cell therapy; cytokine release syndrome; fever; mTOR; metabolic fitness; mitochondrial function; translation initiation
    DOI:  https://doi.org/10.1016/j.cmet.2026.10.001
  29. Hepatol Commun. 2026 Nov 01. pii: e1075. [Epub ahead of print]10(11):
    Adaptive immune plasticity in MASH: Functional states, pathological consequences, and regulatory mechanisms.
    Xiayu Yu, Yuxuan Yang, Lan Bai.
      Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease driven by both metabolic stress and immune dysregulation. A growing body of evidence suggests that adaptive immune cells exhibit significant functional plasticity during the progression and resolution of MASH. CD8+ T cells can assume various states, including pathogenic cytotoxicity, functional exhaustion, and tissue repair; CD4+ T cells exhibit enhanced Th1/Th17 programming, reduced Treg stability, and a functional shift toward Th17/Treg; and B cells undergo remodeling between regulatory, pro-inflammatory, and antibody-effect states. These functional states determine disease outcomes through distinct effector mechanisms. The cytotoxicity and inflammatory factors of pathogenic T cells promote hepatocyte damage, metabolic dysregulation, and hepatocyte stellate cell activation, while B-cell antigen presentation, cytokine, and antibody responses further amplify inflammation and fibrosis; conversely, Tregs, Bregs, and tissue-resident CD8+ T cells with reparative functions can limit inflammation or promote the resolution of fibrosis. Adaptive immune plasticity is, in turn, continuously shaped by the hepatic metabolic environment, in which glycolipid and mitochondrial metabolic reprogramming determine the metabolic basis of different functional states, while metabolite-driven epigenetic remodeling stabilizes corresponding transcriptional programs. Microbiome components and metabolic signals originating from the gut-liver axis further regulate the state of T and B cells within the liver. Consequently, the functional states of adaptive immune cells, their pathological effects, and their metabolic regulation collectively constitute a critical immunometabolic network linking metabolic dysregulation, chronic inflammation, and the progression of fibrosis, providing a unified mechanistic framework for understanding the sustained progression of MASH and tissue repair.
    Keywords:  B-lymphocytes; T-lymphocytes; energy metabolism; epigenetics; metabolic reprogramming
    DOI:  https://doi.org/10.1097/HC9.0000000000001075
  30. Nature. 2026 Oct 28.
    Tumour assembloids recapitulate tumour-CAF-T cell crosstalk in renal cancer.
    Eunjee Kim, Minyong Kang, Jang Hee Han, Juhee Lee, Yunhee Kim, Chang Wook Jeong, HyeSun Lee, Hyun Je Kim, Kunyoo Shin.
      Dynamic interactions between tumours and their microenvironment are crucial for cancer progression and therapeutic outcomes1,2. However, our understanding of these relationships remains limited by the constrained capacity of current human model systems to manipulate diverse cellular components and to interrogate complex tumour-stroma crosstalk. Here we generated combinatorial, mix-and-match tumour assembloids by conditionally reconstituting multiple components of human renal cell carcinoma, including cancer cells, cancer-associated fibroblasts (CAFs) and tumour-infiltrating immune cells. Using genetically engineered renal cell carcinoma assembloids with humanized mouse models, we uncovered mechanisms by which CAFs coordinate interactions between tumour cells and CD8+ T cells to maintain non-cell-autonomous CD8+ T cell stemness and drive responsiveness to anti-PD-1 therapy. These interactions operate through a tumour-CAF-T cell signalling axis in which tumour-derived WNT induces CAF expression of activin A, which enhances CD8+ T cell stemness and sensitivity to PD-1 blockade. In non-responders, we also identified a subset of WNT-unresponsive CAFs that do not produce activin A, which leads to impaired CD8+ T cell stemness and resistance to therapy. Together, these findings establish a tumour-CAF-T cell axis as a key determinant of heterogeneous responses to immune checkpoint inhibitors. Moreover, tumour assembloids provide a versatile platform for mechanistic dissection of the tumour microenvironment and evaluation of personalized immunotherapy strategies.
    DOI:  https://doi.org/10.1038/s41586-026-11208-w
  31. Nat Rev Immunol. 2026 Oct 28.
    Granzyme K-expressing CD8+ T cells, complement activation and histotoxic immunity.
    Xin Liu, Hai Qi.
      Cytotoxic CD8+ T cells induce target-cell death by producing effector proteases called granzymes. Most granzymes, as exemplified by granzyme B, induce apoptosis by cleaving intracellular substrates after delivery to target cells via the immunological synapse. By contrast, it was recently shown that granzyme K (GZMK), which is selectively expressed by a unique population of CD8+ T cells, activates the complement cascade instead of executing direct cytotoxicity. In this Perspective, we summarize recent data on complement activation by CD8+ T cell-derived GZMK that points to a novel lymphocyte-mediated pathway of complement activation. We present evidence that GZMK-expressing CD8+ T cells have distinct pro-inflammatory effects in tissues and discuss their involvement in an array of chronic and inflammatory diseases. Furthermore, we propose the concept of 'tissue histotoxicity' as a core feature of GZMK-expressing CD8+ T cells. We suggest this as a defence strategy that enables the immune system to act on a tissue neighbourhood instead of targeting one cell at a time. Finally, we discuss the possibility of GZMK expression being a heritable trait in subsets of memory T cells.
    DOI:  https://doi.org/10.1038/s41577-026-01364-5
  32. Aging Cell. 2026 Nov;pii: e70780. [Epub ahead of print]25(11):
    Senescent Mesenchymal Stromal Cells Drive Stem Cell Aging Through Dysregulated Chemokine Synthesis.
    Shaianne N Stein, Lorena R Braid.
      Aging is accompanied by a progressive decline in tissue regenerative capacity, driven by intrinsic stem cell dysfunction and age-associated deterioration of the surrounding stem cell niche. Mesenchymal stromal cells (MSCs) are ubiquitous components of stem cell niches, where they integrate structural, metabolic, inflammatory, and paracrine cues to regulate stem cell quiescence, activation, and differentiation. With age, MSCs undergo functional decline and senescence, altering their secretory and signaling profiles. Across tissues, MSC senescence emerges as an intermediate amplifier of aging: molecular, metabolic, epigenetic, and inflammatory stressors promote the senescent state, which converts these upstream insults into chemokine imbalance, chronic inflammation, and progressive loss of stem cell support. Here, we synthesize classical and emerging literature to examine how age-associated changes in MSC chemokine synthesis contribute to stem cell aging, and we propose a synthesis-based model in which MSCs translate age-associated stressors into altered chemokine repertoires that disrupt stem cell-supportive signaling. We also discuss therapeutic strategies, including chemokine-directed therapies, senolytics, and MSC rejuvenation, that may restore regenerative capacity by normalizing MSC-derived signals. Together, the evidence identifies dysregulated chemokine synthesis as a conserved mechanism linking tissue-resident MSC aging to declining regenerative capacity.
    Keywords:  aging; chemokines; inflammaging; mesenchymal stromal cells; rejuvenation; senescence; stem cells
    DOI:  https://doi.org/10.1111/acel.70780
  33. Biomedicines. 2026 Oct 06. pii: 2258. [Epub ahead of print]14(10):
    Metabolic Rewiring of GPC3-Targeted CAR T Cells Expressing IL-15 and HER2-Targeted CAR T Cells via the ADA1-CD26 Axis Promotes Tumor Infiltration and Limits Systemic Toxicities.
    Yue Hu, Kevin Song, Ruoning Wang, Stephen Gottschalk, Andras Heczey, Xiaotong Song.
      Background: Chimeric antigen receptor (CAR) T-cell therapy for solid tumors is limited by inadequate T-cell persistence and tumor infiltration, as well as treatment-associated cytokine release syndrome (CRS). To address these challenges, we developed a metabolically rewired CAR T-cell (MRCAR) platform by co-expressing adenosine deaminase 1 (ADA1) and CD26 in CAR T cells. Methods: MRCAR T cells were generated using either GPC3-targeted CARs for hepatocellular carcinoma (HCC) or HER2-targeted CARs for breast cancer. For HCC, we further evaluated constructs with and without enforced IL-15 expression to boost T-cell function. Results: In vitro, IL-15-expressing GPC3-MRCAR T cells exhibited enhanced proliferation, sustained effector function, reduced exhaustion, and superior cytotoxicity following repeated antigen stimulation compared with conventional CAR T cells. CD26 expression significantly enhanced CAR T-cell invasiveness in transwell assays and promoted tumor infiltration in vivo in both tumor models. ADA1 expression enhanced CAR T-cell persistence and was associated with increased frequencies of memory and stem-like T-cell populations in vivo. Notably, although IL15-GPC3-CAR T-cell treatment increased antitumor activity, it also caused high mortality and systemic inflammation in Huh7 tumor-bearing mice, whereas incorporation of ADA1 and CD26 into MRCAR T cells significantly improved survival and reduced serum levels of IL-6, IFN-γ, and TNF-α. Mechanistically, conventional IL-15-expressing GPC3-CAR T cells induced proinflammatory M1-like macrophage activation, whereas MRCAR T cells markedly suppressed this inflammatory response. Conclusions: Collectively, these results indicate that metabolic rewiring via ADA1 and CD26 enhances CAR T-cell expansion, tumor infiltration, persistence, and safety, supporting the MRCAR platform as a promising strategy to improve both efficacy and tolerability of CAR T-cell therapy for solid tumors.
    Keywords:  ADA1; CAR T cell; CD26; IL-15; cytokine release syndrome; inflammation; invasion; macrophage polarization; memory T cells; persistence; solid tumor
    DOI:  https://doi.org/10.3390/biomedicines14102258
  34. Nat Cancer. 2026 Oct 30.
    BAZ2A-induced epigenetic states in cancer cells fuel palmitate accumulation in the tumor microenvironment driving CAR-T cell exhaustion.
    Hongye Wang, Haigang Geng, Jingtong Zhao, Haodong Ge, Yan Shen, Zhaorong Wu, Linke Bian, Jinlu Zuo, Zhen Sun, Ying Yang, Jiufei Zhu, Weiming Shen, Jiaojiao Zheng, Dan Cui, Jiawei Ding, Shuxian Yang, Hongchao He, Hai Huang, Yi Gao, Keke Gao, Mengfei Huo, Hanqing Liu, Yixun Liu, Jun Xiao, Dan-Feng Xu, Qiang He, Yihao Zhang, Feng Liu, Lianxin Liu, Minghua Zheng, Haojie Jin, Bo Zhai, Chuanjie Zhang.
      Chimeric antigen receptor T (CAR-T) cell therapy shows limited efficacy in solid tumors, partly owing to poorly defined tumor-intrinsic resistance mechanisms. Here we show that the epigenetic regulator BAZ2A drives resistance to CD70-targeted CAR-T therapy by reprogramming tumor lipid metabolism. Using an in vivo CRISPR screen in a mouse renal cell carcinoma model, we identify BAZ2A as a key mediator that promotes the production and accumulation of palmitic acid, a saturated fatty acid in the tumor microenvironment. Excess palmitic acid is taken up by CAR-T cells and impairs mitochondrial fitness by inhibiting PGC-1α activity, thereby enforcing a dysfunctional state. Pharmacologic inhibition of BAZ2A reduces lipid accumulation and restores CAR-T cell activity in vivo. These findings reveal an epigenetic-metabolic mechanism of immune resistance and suggest that targeting tumor lipid remodeling represents a therapeutic strategy to overcome CAR-T resistance in solid tumors.
    DOI:  https://doi.org/10.1038/s43018-026-01267-3
  35. Oncogene. 2026 Oct 27.
    Targeting exosomal circSENP5 prevents immune escape of macrophages in pMMR-CRC via regulating mitochondrial metabolism.
    Yanxin Xu, Kaibo Li, Yang Liu, Jikang Wang, Wenkang Wang, Fei Han, Ming Yue, Changjiang Zhou, Lin Gan, Xiaofei Duan, Weilong Chang, Gangcheng Wang, Junhong Hu, Zhenqiang Sun.
      Proficient mismatch repair colorectal cancer (pMMR-CRC) exhibits resistance to immunotherapy, presenting a significant clinical challenge that must be addressed. Exosomes, which serve as mediators of intercellular communication, play a crucial role in the tumor microenvironment (TME). However, the mechanisms that exosomes regulate tumor immunity in pMMR-CRC need to be fully elucidated. In this study, we discovered that circSENP5, a circular RNA (circRNA), is highly expressed in pMMR-CRC and is derived from exosomes that are transferred to tumor-associated macrophages (TAMs). This transfer enhances the oxidative phosphorylation of macrophages and promotes immunosuppressive characteristics, as well as increased levels of inhibitory receptors on CD8+ T cells. Mechanistically, circSENP5 binds to the deubiquitinase USP10, stabilizing LRPPRC, a key regulator of mitochondrial function. This interaction protects LRPPRC from ubiquitin-mediated degradation, resulting in enhanced mitochondrial respiration and immune suppression. in vivo, the overexpression of circSENP5 accelerates tumor progression, while its mutation disrupts the interaction with USP10, leading to reduced TAM infiltration and improved CD8+ T cell function. Targeting circSENP5 in combination with anti-PD-L1 immune checkpoint therapy effectively suppresses tumor progression, highlighting a potential therapeutic strategy. These findings suggest that exosomal circSENP5 plays a pivotal role in immune evasion in pMMR-CRC by modulating mitochondrial metabolism in TAMs, thereby providing potential therapeutic targets for overcoming immune resistance in pMMR-CRC.
    DOI:  https://doi.org/10.1038/s41388-026-04040-z
  36. Nat Commun. 2026 09 25. pii: 11144. [Epub ahead of print]17(1):
    SIRPγ promotes CD8⁺ T cell exhaustion via metabolic-epigenetic reprogramming in tuberculous pleural effusion.
    Yuening Yang, Qianqian Xue, Sidao Wang, Wenbei Peng, Linlin Ye, Bohan Yang, Zihao Wang, Xuan Xiang, Haolei Wang, Yiran Niu, Hai Huang, Chengqing Yang, Qiong Zhou.
      Previous studies have shown that signal regulatory protein γ (SIRPγ) is an important regulatory factor for T cell function. However, its expression and biological role in tuberculous pleural effusion (TPE) remain unknown. In this study, we find that the level of SIRPγ is significantly upregulated in TPE compared to non-TPE. Furthermore, we demonstrate SIRPγ involvement in TPE pathogenesis through the induction of CD8⁺ T cell exhaustion. Mechanistically, SIRPγ interacts with CD47 to activate the phosphatidylinositol 3/kinase-protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway, leading to the upregulation of phosphoglycerate dehydrogenase (PHGDH) and the enhancement of serine metabolism. Serine, in turn, facilitates S-adenosylmethionine (SAM)-dependent trimethylation of histone H3 lysine 4 (H3K4me3) epigenetic modification at the NFATC2 locus. This modification, in coordination with TCR-induced calcium signaling, promotes NFATC2 activation, ultimately driving the expression of exhaustion-associated transcription factors and immunosuppressive receptors. Together, our findings identify SIRPγ as a regulator of CD8⁺ T cell exhaustion in TPE and suggest its potential as a predictive biomarker for TPE diagnosis.
    DOI:  https://doi.org/10.1038/s41467-026-77779-4
  37. Int J Nanomedicine. 2026 ;21 650413
    A Narrative Review of Nanomedicine in Cancer Therapy: Modulating Metabolic Reprogramming to Enhance Immunotherapy.
    Hongpeng Wu, Fengyi Wang, Wei Sun, Hao Zhang.
       Background: Metabolic reprogramming of tumor cells interacts with functional alterations of immune cells to establish an immunosuppressive tumor microenvironment, which constrains the efficacy of immunotherapy. Nanomedicine provides technical approaches for targeted delivery and controlled release of metabolic modulators.
    Main Text: This review outlines major nanocarriers and their design principles, dissects the crosstalk among glucose, amino acid and lipid metabolism, and illustrates how nutrient competition and metabolic byproducts shape antitumor immune responses. It focuses on summarizing advances in nanodelivery strategies targeting these metabolic pathways and their combinatorial application with immunotherapy.
    Conclusion: Nanomedicine-mediated metabolic intervention holds promise for remodeling the tumor immune microenvironment. However, tumor cells and effector T cells share partial metabolic requirements, and nonselective inhibition may impair antitumor immunity. Improving the cell selectivity of interventions and validating long-term safety and clinical benefits represent key considerations for future translational research.
    Keywords:  cancer therapy; immunotherapy; metabolic reprogramming; nanomedicine
    DOI:  https://doi.org/10.2147/IJN.S650413
  38. Front Mol Biosci. 2026 ;13 1990670
    SIRT2 in metabolism, aging, and longevity.
    Menghui Li, Yihuan Dong, Wen Ren, Weixia Dong, Shaoping Ji.
      SIRT2, an NAD+-dependent deacetylase, is increasingly recognized as an important regulator of cellular metabolism and aging. By deacetylating diverse substrates, SIRT2 influences glucose metabolism, lipid metabolism, mitochondrial function, cytoskeletal dynamics, oxidative stress, and inflammatory responses, thereby contributing to cellular metabolic homeostasis and aging. Emerging evidence suggests that age-related alterations in NAD+ metabolism may affect SIRT2 activity and disrupt these processes, potentially promoting metabolic dysfunction, mitochondrial impairment, cellular senescence, and chronic inflammation. In addition, the effects of SIRT2 on aging appear to be highly context- and tissue-dependent, and its precise contribution to organismal longevity remains incompletely understood. In this review, we primarily focus on the role of SIRT2 in aging and longevity through the regulation of energy metabolism, with particular emphasis on the underlying molecular mechanisms and its interactions with metabolic and stress-responsive pathways. Understanding these mechanisms and regulations may provide new insights into SIRT2 biology and potential strategies for maintaining metabolic homeostasis and promoting healthy aging, even applications in clinic practice.
    Keywords:  SIRT2; aging; energy metabolism; lifespan; metabolic homeostasis
    DOI:  https://doi.org/10.3389/fmolb.2026.1990670
  39. bioRxiv. 2026 Oct 07. pii: 2026.10.06.757085. [Epub ahead of print]
    Adenosylhomocysteinase drives epigenetic and metabolic reprogramming in ZFTA-RELA ependymoma.
    Navneesh Yadav, Olivia Pelcher, Raja G R Mooli, Robert B Cameron, Alberto Delaidelli, Kannan B N Rao, Bhagyalakshmi Manikandan, Senna Visser, Antonio C T Cobos, Vishal Parmar, Yuvraj Kayola, Siva K Natarajan, Yash Patel, Jiao Zhang, Hardik Shah, Subrahmanya D Vallabhapurapu, Saifur R Khan, Aaron Y Mochizuki, Kalil G Abdullah, Baoli Hu, Calixto-Hope G Lucas, Philipp Sievers, Felix Sahm, Andrew M Donson, Nicholas K Foreman, Martine F Roussel, Thomas M Pearce, Peter Dirks, Kristian W Pajtler, Stephen C Mack, Jeremy Rich, Richard J Gilbertson, Eric C Holland, Sadeesh K Ramakrishnan, Taylor J Abel, Srinivas Ramachandran, Sameer Agnihotri, Bokai Zhu, Sriram Venneti, Brandon Faubert, Michael D Taylor, Esther Hulleman, Ian F Pollack, Timothy Phoenix, Kulandaimanuvel Antony Michealraj.
      Supratentorial ependymomas (ST-EPNs) are aggressive pediatric brain tumors predominantly driven by the recurrent ZFTA-RELA fusion, an oncogenic chromatin regulator that establishes an aberrant transcriptional program. Although metabolic pathways modulate epigenetic regulation by controlling the availability of metabolic cofactors, how ZFTA-RELA coordinates metabolic reprogramming with epigenetic regulation is not well understood. Here, we show that ZFTA-RELA-positive ependymomas exhibit enhanced methionine dependency, elevated adenosyl homocysteinase (AHCY) expression, and epigenetically control aspartate metabolism for tumor growth. Mechanistically, ZFTA-RELA upregulates AHCY, increasing cellular methylation potential which promotes H3K4me3-dependent expression of CAD, the first enzyme complex of de novo pyrimidine biosynthesis, while simultaneously enforcing H3K27me3 mediated repression of ASNS, which encodes asparagine synthetase. Through this coordinated epigenetic program, aspartate utilization is directed toward pyrimidine biosynthesis while endogenous asparagine production is limited. Restricting S-adenosylmethionine availability or genetically or pharmacologically inhibiting AHCY reverses these epigenetic states, leading to CAD downregulation, ASNS upregulation, impaired nucleotide synthesis, and suppression of tumor growth in vitro and in vivo. Similarly, EZH2 inhibition also restores ASNS expression and suppresses tumor proliferation. These findings suggest that ZFTA-RELA EPN maintain ASNS-low phenotype which conditionally make them dependent on extracellular asparagine. We further show that enhanced de novo pyrimidine synthesis not only supports nucleotide production but also provides UDP-sugars required for N-glycosylation and stabilization of the asparagine transporter SLC1A5, thereby promoting extracellular asparagine uptake and tumor proliferation. Collectively, our findings identify AHCY as a critical metabolic regulator of epigenetic and metabolic reprogramming that drives pyrimidine synthesis and establishes extracellular asparagine dependency, revealing actionable metabolic vulnerabilities in ZFTA-RELA-positive ST-EPNs.
    Abstract Figure:
    Key Findings: ZFTA-RELA fusion drives aspartate metabolic reprogramming through chromatin regulationAdenosylhomocysteinase (AHCY) epigenetically enhance de novo pyrimidine synthesis and suppress endogenous asparagine synthesis ZFTA-RELA EPNs exhibit ASNS low phenotype and dependence on extracellular asparagine Enhanced de novo pyrimidine biosynthesis fuels nucleotide synthesis and SLC1A5-dependent asparagine uptakeTargeting de novo pyrimidine biosynthesis and depleting extracellular asparagine reveal actionable vulnerabilities in ZFTA-RELA ST-EPN.
    DOI:  https://doi.org/10.64898/2026.10.06.757085
  40. Proc Natl Acad Sci U S A. 2026 Nov 03. 123(44): e2610110123
    Hepatitis C viral variants bear signatures of de novo CD8+ T cell and antibody pressure after spontaneous postpartum viral suppression.
    Christopher C Phelps, Stephanie Smith, John Gridley, Jennifer A Kohout, Zhaohui Xu, Joseph Marcotrigiano, Kara Rood, Nicole E Skinner, Arash Grakoui, Jonathan R Honegger, Christopher M Walker.
      Progression to chronic hepatitis C virus (HCV) infection entails loss of HCV-specific CD4+ T cell help, emergence of viral variants that escape recognition by CD8+ T cells and neutralizing antibodies, and exhaustion of CD8+ T cells targeting remaining intact epitopes. Once chronic infection has been established, it is generally lifelong without treatment. However, in some chronically infected women, a surprising postpartum viral load decline has been linked to resurgent functional HCV-specific CD4+ helper T cells. A minority of women even spontaneously clear long-standing chronic infection postpartum. To test whether restored T cell help boosts HCV-specific CD8+ T cell or antibody responses in women with postpartum viral control, we performed serial near-full-length deep sequencing of HCV genomes to assess evolution of viral MHC class I epitopes and antibody epitopes in nine women with significant postpartum viral declines (≥ 1 log10 at 3 mo postpartum, "controllers") and 12 with more stable levels ("noncontrollers"). Although not associated with mutations arising early postpartum, at 12 to 24 mo postpartum, viral control was strongly associated with amino acid mutations in epitopes predicted to be targeted by CD8+ T cells and neutralizing antibodies. Plasma from controllers also demonstrated a postpartum increase in neutralization of multiple HCV strains. Together, these findings support the hypothesis that postpartum viral control is mediated by CD8+ T cell and antibody pressure.
    Keywords:  T cell; hepatitis C virus; neutralizing antibodies; pregnancy; viral sequencing
    DOI:  https://doi.org/10.1073/pnas.2610110123
  41. Cell Commun Signal. 2026 Jul 29. pii: 577. [Epub ahead of print]24(1):
    Neutrophil metabolic heterogeneity as a novel target in diseases.
    Yuting Zhang, Minjie Guo, Danni Zhao, Hele Liu, Xuanyin Ding, Xiao Yuan, Ying Jiang, Dan Feng, Xu Wang.
       BACKGROUND: Neutrophils, pivotal effector cells of the immune system, are increasingly recognized to have considerable functional and phenotypic heterogeneity. The emergence of immunometabolism has offered a framework for understanding this diversity. Accumulating evidence indicates that shifts in metabolic pathways and their byproducts can reshape the fate and function of neutrophils.
    MAIN BODY: Neutrophil heterogeneity arises from both distinct developmental stages and specific signals within peripheral tissue microenvironments. Functionally, glycolysis is the central metabolic pathway that fuels core effector responses, while metabolites such as lactate, lipids, and amino acids can further modulate neutrophil phenotypes. In pathological contexts of metabolic dysregulation, metabolic stress induces extensive reprogramming of neutrophils. This process drives the accumulation of specific metabolites, which in turn trigger transcriptional reprogramming through epigenetic remodeling, establishing a self-reinforcing loop that sustains pro-pathological neutrophil states. Targeting key nodes within these dysregulated metabolic pathways has potential as a therapeutic strategy.
    CONCLUSIONS: Here, we review the metabolic heterogeneity of neutrophil subpopulations and the mechanisms by which distinct metabolic programs drive disease progression in pathological settings. We further discuss current therapeutic strategies targeting these pathways. Through this analysis, we aim to provide a refined perspective on the immune landscape and to identify new possibilities for therapeutic intervention.
    Keywords:  Heterogeneity; Immunometabolism; Neutrophils; Transcriptomics; Tumor-associated neutrophils
    DOI:  https://doi.org/10.1186/s12964-026-03112-7
  42. Nat Cancer. 2026 Oct 30.
    Targeting GALE harnesses γδ T cells for cancer immunotherapy.
    Jana L Raynor, Hongbo Chi.
      
    DOI:  https://doi.org/10.1038/s43018-026-01203-5
  43. Cancer Genet. 2026 Oct 09. pii: S2210-7762(26)00119-5. [Epub ahead of print]308-309 249-262
    Spatiotemporal immune remodeling by light at night uncovers an adaptive immune signature linked to tumor progression and anti-PD-1 non-response.
    Kai Cheng, Ruijiao Kong, Hui Zhang, Zhiwen Nie, Qian Gao, Chenfei Du, Leiming Cai, Qian Li, Shanrong Liu, Huiming Sheng.
      Circadian disruption, notably induced by light at night (LAN), is increasingly recognized as a modulator of systemic immune function; however, its high-resolution spatiotemporal impact and relevance to cancer immunotherapy remain poorly defined. Here, we constructed a spatiotemporal single-cell transcriptomic atlas of murine lymph nodes, peripheral blood, and spleen across circadian time points to dissect the immunological consequences of LAN exposure. We observed that LAN exposure was associated with profound, tissue-specific transcriptional remodeling of the adaptive immune system. Specifically, B cells exhibited suppressed circadian clock programs and impaired homing and retention signatures. Concurrently, CD8+ T cells exhibited transcriptional profiles consistent with an aberrantly activated, late-effector state, a transition accompanied by altered intercellular MHC-I communication. To evaluate the translational relevance of these transcriptomic shifts, we developed a computational LAN Immune Dyssynchrony Score (LAN-IDS) and projected these murine-derived signatures onto human cancer cohorts. In human melanoma sentinel lymph nodes, the LAN-associated CD8+ T cell trajectory exhibited strong directional concordance with advanced (Stage III) disease. Crucially, interrogating these signatures within a clinical melanoma cohort revealed that the aberrantly activated CD8+ T cell program is significantly elevated in patients with primary resistance to anti-PD-1 immunotherapy. Collectively, our cross-species computational analysis identifies a spatiotemporal adaptive immune dyssynchrony signature. These findings identify specific lymphocyte transcriptional states that may serve as candidate correlates of tumor progression and immunotherapy non-response.
    Keywords:  Adaptive immunity; Circadian disruption; Immunotherapy resistance; Melanoma; Single-cell transcriptomics
    DOI:  https://doi.org/10.1016/j.cancergen.2026.10.003
  44. J Clin Invest. 2026 Oct 27. pii: e204359. [Epub ahead of print]
    Attenuating NKG2D stimulation reshapes intratumoral NK cell functional state to enhance persistence and anti-tumor efficacy.
    Sizhe Liu, Ryan J Brown, Payal Dhar, Geetha Priyanka Yerradoddi, Tyler A Smith, Bin Zhang, Deyu Fang, Congcong He, David J VanderWeele, Masha Kocherginsky, Arabela Grigorescu, Seth M Pollack, Qingshu Meng, Qi Cao, Karla Guerra, Weiguo Cui, Jennifer D Wu.
      NK cell-based therapies for solid tumors are limited by poor persistence and progressive functional impairment. Here, we investigated how the strength of NKG2D stimulation shapes NK cell fate and therapeutic efficacy. Using B10G5, a MICA/B-targeting partial agonist antibody that attenuates NKG2D stimulation, we show that reduced NKG2D stimulation reshapes the intratumoral NK cell compartment by enriching EOMEShiTCF1hi stem-like NK (stemNK) cell pool, preserving functional diversity, and limiting mitochondrial oxidative stress and exhaustion induced by chronic sMIC/MIC exposure. Mechanistically, we identified the H3K27me3 demethylase KDM6B as a conserved regulator of NK cell stemness whose enzymatic activity is required to maintain the intratumoral stemNK cell pool. Conversely, strong NKG2D stimulation induced mitochondrial ROS accumulation and upregulated the inhibitory receptor LAG3 on NK cells. Attenuated NKG2D stimulation on human NK cells increased KDM6B expression and reduced repressive H3K27me3 mark at the TCF7 locus. Importantly, attenuated NKG2D stimulation during ex vivo expansion enhanced human NK cell in vivo persistence and antitumor efficacy following adoptive transfer. Together, these findings establish NKG2D stimulation strength as a key determinant of NK cell fate and function in solid tumors and identify a translatable concept to improve NK cell-based immunotherapy for solid tumors.
    Keywords:  Cancer immunotherapy; Immunology; NK cells; Oncology
    DOI:  https://doi.org/10.1172/JCI204359
  45. bioRxiv. 2026 Sep 01. pii: 2026.08.28.747758. [Epub ahead of print]
    A mechanistic basis for CD8+ T cell expansion sensitivity as a predictor of HIV post-treatment control.
    Tin Phan, Nicole Pagane, Jasmine Kreig, Aurelien Marc, Macauley Locke, Michael J Peluso, Demi A Sandel, Amelia N Deitchman, Rachel L Rutishauser, Steven G Deeks, Ruian Ke, Ruy M Ribeiro, Alan S Perelson.
      A key goal in HIV-1 cure research is to understand why some individuals control viral rebound after stopping antiretroviral therapy (ART). Recent human studies have identified responding CD8+ T cells expressing Ki-67 and the transcription factor TCF-1 as correlates of post-treatment control, but the mechanistic basis of this association remains unclear. Using the theoretical framework of Conway and Perelson, we fit mechanistic within-host models to viral load and CD8+ T cell data from 9 individuals in a combination immunotherapy trial following ART interruption. Although Ki-67 and TCF-1 measurements were not used for fitting, the inferred effector cell expansion sensitivity, i.e., the responsiveness of effector expansion to low antigen levels, shows a strong linear relationship with Ki-67 and TCF-1 levels at rebound (Pearson's r ≈ 0.8). Building on this, we show analytically that the post-rebound viral load set point is inversely proportional to the effector cell expansion sensitivity, and thus strongly correlates with cycling (Ki-67+) CD8+ T cells (r ≈ -0.8) at rebound, and a subset that expresses TCF-1 (r ≈ -0.9). In effect, individuals with a larger proportion of CD8+ T cells responding to viral rebound, and a greater representation of TCF-1 expressing cells within the responding subset, achieve markedly lower viral set points through a higher effector cell expansion sensitivity. This mechanism is consistent with prior modeling in a non-intervention ATI setting, suggesting it may generalize across more rebound contexts. Our results provide a mechanistic explanation why both Ki-67+ responding CD8+ T cells and their TCF-1-expressing subset predict post-treatment control, linking clinical correlation to its underlying cause and highlighting Ki-67 and TCF-1 as potential early biomarkers of HIV immunotherapy success.
    DOI:  https://doi.org/10.64898/2026.08.28.747758
  46. Methods Mol Biol. 2027 ;3089 591-601
    Generation of Murine Chimeric Antigen Receptor T Cells for Adoptive T Cell Therapy for Melanoma.
    Amorette Barber.
      Expression of chimeric antigen receptors enables T cells to be redirected toward melanoma-associated antigens in an MHC-independent manner. Retroviral transduction can be used to introduce these receptor constructs into murine CD4⁺ and CD8⁺ T cells. Here, we outline the generation of retroviral supernatants and the activation, transduction, expansion, and selection of murine T cells expressing the chimeric-PD1 receptor. This protocol can be adapted for any murine chimeric antigen receptor construct.
    Keywords:  Chimeric antigen receptor; Immunotherapy; Melanoma; Mouse; Retroviral transduction; T cell
    DOI:  https://doi.org/10.1007/978-1-0716-5619-8_39
  47. Med Pr. 2026 Oct 21. pii: 241797. [Epub ahead of print]
    [Editorial].
    Alicja Bortkiewicz.
      
    Keywords:  accessibility; aging; ergonomics of older age; healthy aging; older adults; work participation
    DOI:  https://doi.org/10.13075/mp.5893.01775
  48. bioRxiv. 2026 Oct 09. pii: 2026.10.02.755737. [Epub ahead of print]
    Repeated malaria exposure reprograms Vδ2+ γδ T cell chromatin accessibility and immune function toward a reversible hyporesponsive state.
    Kathleen D Press, Midhuna I Joseph Maran, Adam Ashkar-Masarwa, Kylie Camanag, Derek Chen, Vida Shokoohi, Arwa Kathiria, Maureen Ty, Jason Nideffer, John Rek, Joaniter Nankabirwa, Felistas Nankya, Julia Schulze-Hentrich, Isaac Ssewanyana, Moses Kamya, Michelle Boyle, Bryan Greenhouse, Grant Dorsey, Margaret Feeney, Will Greenleaf, Sandy Klemm, Fabian Müller, Prasanna Jagannathan.
      Vδ2+ γδ T cells contribute to antimalarial immunity via pro-inflammatory and cytotoxic mechanisms. Among children who have experienced repeated episodes of malaria, Vδ2+ T cells develop reduced pro-inflammatory function through mechanisms that remain unknown. We hypothesized that recurrent malaria drives coordinated epigenetic and transcriptional remodeling of these semi-innate cells. Using PBMC from Ugandan children in cohorts spanning high and low transmission (10 children) and longitudinally across a marked decline in transmission (20 children, 3 timepoints), we profiled the epigenome and transcriptome of Vδ2+ T cells by paired bulk ATAC-seq and RNA-seq and by CITE-seq. Higher malaria exposure was associated with reduced Vδ2+ T cell TNFα and IFNγ production and with thousands of differentially accessible chromatin regions. Immunoregulatory genes including LYN, PLCG2, and HAVCR2 (Tim-3) showed increased chromatin accessibility and/or expression at high exposure, whereas pro-inflammatory gene (IFNG, GZMK, IL7R) and AP-1 (JUN/FOS) motif accessibility were increased at low exposure; linkage of regulatory elements with target genes corroborated these associations. Single-cell transcriptional analysis identified a cytotoxic CD8+CD16+CD57+ Vδ2+ T cell subset. In our in vitro model, repeated stimulation with malaria-infected red blood cells or the phosphoantigen HMBPP was similarly associated with reduced Vδ2+ T cell degranulation and cytokine production. Diminished responsiveness was predominantly TCR-dependent, accompanied by heightened p38 signaling, and was partially reversed by rest induced by the tyrosine kinase inhibitor dasatinib. Together these data reveal how repeated malaria may reshape cellular immunity by reprogramming Vδ2+ T cells toward a reversible, hyporesponsive state and highlight targets for therapeutically restoring their function.
    DOI:  https://doi.org/10.64898/2026.10.02.755737
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