bims-imseme 2025-10-19 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2025–10–19
24 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Nutrient allocation fuels T cell-mediated immunity.
Heme and iron toxicity in the aged spleen impairs T cell immunity through iron deprivation.
CMTR1 directs mitochondrial dynamics during T cell activation through epitranscriptomic regulation of splice isoforms.
Burning the candle at both ends: ROS-mediated telomere damage drives T cell dysfunction.
Preservation of Autophagy May Be a Mechanism Behind Healthy Aging.
T cell immunity in glioma and potential implications for immunotherapy: a systematic review.
Metabolic Reprogramming and CD8+ T-Cell Exhaustion During Chronic HBV Infection.
Tumor-associated macrophages: untapped molecular targets to improve T cell-based immunotherapy.
Zinc finger protein Zfp335 is required for T cell homeostatic proliferation through regulating Lmnb1.
Envirotune-CAR-T: a hypoxia-responsive and glutamine-enhanced CAR-T cell therapy for overcoming tumor microenvironment-mediated suppression.
The co-inhibitory receptor TIGIT promotes tissue-protective functions in T cells.
Fat talks first: how adipose tissue sets the pace of aging?
Microenvironmental regulation of solid tumour resistance to CAR T cell therapy.
Aged mice exhibit widespread metabolic changes but preserved major fluxes.
Single-cell transcriptome analysis reveals the potential heterogeneous mechanism of CD8+ T cell immune dysfunction in thyroid cancer.
Single-cell clonal lineage tracing identifies the transcriptional program controlling the cell-fate decisions by neoantigen-specific CD8+ T cells.
TCR signal-enhancing mutation alters lipid metabolism of thymocytes and impairs antitumor immunity of mature T cells.
Endoplasmic reticulum stress orchestrates tumor metabolism and immunity: new insights into immunometabolic therapeutics.
Identification of antigen-specific functional CD8+ T cells using an optofluidic system independent of epitope information.
Resident memory T cells call the shots in tissue immunity.
Targeting PURPL RNA enabled rejuvenation of senescence cells via epigenetic reprogramming.
Sargentodoxa cuneata suppresses lung adenocarcinoma progression by enhancing cytotoxic CD8+ T activity through the ACY1/ARG2 interaction.
Enhanced FOS expression improves tumor clearance and resists exhaustion in NR4A3-deficient CAR T cells under chronic antigen exposure.
Mitochondrial dynamics and metabolic attributes regulate function of natural killer cell and infiltration in tumor microenvironment modulating disease progression.

Cell Metab. 2025 Oct 15. pii: S1550-4131(25)00393-6. [Epub ahead of print]

Nutrient allocation fuels T cell-mediated immunity.

Joseph Longo, McLane J Watson, Kelsey S Williams, Ryan D Sheldon, Russell G Jones.

  T cell activation and function are intricately linked to metabolic reprogramming. The classic view of T cell metabolic reprogramming centers on glucose as the dominant bioenergetic fuel, where T cell receptor (TCR) stimulation promotes a metabolic switch from relying primarily on oxidative phosphorylation (OXPHOS) for energy production to aerobic glycolysis (i.e., the Warburg effect). More recently, studies have revealed this classic model to be overly simplistic. Activated T cells run both glycolysis and OXPHOS programs concurrently, allocating diverse nutrient sources toward distinct biosynthetic and bioenergetic fates. Moreover, studies of T cell metabolism in vivo and ex vivo highlight that physiologic nutrient availability influences how glucose is allocated by T cells to fuel both optimal proliferation and effector function. Here, we summarize recent advancements that support a revised model of effector T cell metabolism, where strategic nutrient allocation fuels optimal T cell-mediated immunity.

Keywords:  T cells; adaptive immunity; effector function; glucose; immunometabolism; nutrient allocation

DOI:  https://doi.org/10.1016/j.cmet.2025.09.008
Nat Aging. 2025 Oct 17.

Heme and iron toxicity in the aged spleen impairs T cell immunity through iron deprivation.

David Ezuz, Heba Ombashe, Lana Watad, Akmaral Rakhymzhanova, Satyarth Pandey, Orna Atar, Esther G Meyron-Holtz, Noga Ron-Harel.

Mechanisms of T cell aging involve cell-intrinsic alterations and interactions with immune and stromal cells. Here we found that splenic T cells exhibit greater functional decline than lymph node T cells within the same aged mouse, prompting investigation into how the aged spleen contributes to T cell aging. Proteomic analysis revealed increased expression of heme detoxification in aged spleen-derived lymphocytes. Exposure to the heme- and iron-rich aged splenic microenvironment induced aging phenotypes in young T cells, including reduced proliferation and CD39 upregulation. T cells survived this hostile niche by maintaining a low labile iron pool, at least in part, via IRP2 downregulation to resist ferroptosis but failed to induce sufficient iron uptake for activation. Iron supplementation enhanced antigen-specific T cell responses in aged mice. This study identifies the aged spleen as a source of hemolytic signals that systemically impair T cell function, underscoring a trade-off between T cell survival and function and implicating iron metabolism in immune aging.

DOI: https://doi.org/10.1038/s43587-025-00981-4
Cell Rep. 2025 Oct 13. pii: S2211-1247(25)01183-0. [Epub ahead of print]44(10): 116412

CMTR1 directs mitochondrial dynamics during T cell activation through epitranscriptomic regulation of splice isoforms.

Alison Galloway, Katarzyna Knop, Carolina Gomez-Moreira, Vanessa Xavier, Sarah Thomson, Harunori Yoshikawa, Olga Suska, Radoslaw Lukoszek, Aneesa Kaskar, Angus I Lamond, Thomas MacVicar, Victoria H Cowling.

  During T cell activation, mitochondrial biogenesis and cellular metabolism are altered to meet the elevated energy demands of protein synthesis, rapid proliferation, and effector T cell function. The mechanisms coupling mitochondrial dynamics to T cell status are unclear. Here, we report that RNA cap methyltransferase 1 (CMTR1) is induced in activated T cells, methylating the first nucleotide on mRNA and U2 small nuclear RNA (snRNA), a component of the spliceosome. Using transcriptomic analyses, we identify a functional splicing module regulating mitochondrial dynamics in T cells, which alters the isoforms of proteins controlling mitochondrial fission and fusion. Through epitranscriptomic control of U2 snRNA and splicing, CMTR1 directs protein isoform selection during T cell activation to promote the development of longer mitochondria with increased respiratory capacity. Thus, CMTR1 upregulation supports the energetic demands of T cell activation, survival, and immune responses.

Keywords:  CMTR1; CP: Immunology; CP: Metabolism; MFF; RNA cap; RNA methylation; T cell; T lymphocyte; metabolism; mitochondria; snRNA; splicing

DOI:  https://doi.org/10.1016/j.celrep.2025.116412
Immunity. 2025 Oct 14. pii: S1074-7613(25)00427-3. [Epub ahead of print]58(10): 2362-2363

Burning the candle at both ends: ROS-mediated telomere damage drives T cell dysfunction.

Alexander J Wesolowski, Rahul Roychoudhuri.

T cells need reactive oxygen species (ROS) for activation and memory formation, yet excessive ROS can drive dysfunction. Rivadeneira et al. show that chronic T cell activation in tumors exposes telomeres to damaging mitochondrial ROS, contributing to T cell dysfunction.

DOI: https://doi.org/10.1016/j.immuni.2025.09.016
Aging Cell. 2025 Oct 13. e70246

Preservation of Autophagy May Be a Mechanism Behind Healthy Aging.

Arsun Bektas, Shepherd H Schurman, Julián Candia, Olaya Santiago-Fernández, Susmita Kaushik, Ana Maria Cuervo, Luigi Ferrucci.

  Autophagy is intricately linked with protective cellular processes, including mitochondrial function, proteostasis, and cellular senescence. Animal studies have indicated that autophagy becomes dysfunctional with aging and may contribute to T cell immunosenescence. In humans, it remains unclear whether autophagy is impaired in CD4+ T cells as people age. To answer this question, we examined basal and inducible autophagic activity in a series of experiments comparing CD4+ T cells from younger (23-35 years old) and older (67-93 years old) healthy donors. We used immunofluorescence to detect LC3 (a marker of autophagosomes and autolysosomes) and LAMP2 (a marker of endolysosomes) in conjunction with bafilomycin A1 (which inhibits the acidification of lysosomes) and CCCP (a mitochondrial uncoupler) to manipulate autophagic flux. We found a significantly higher autophagy flux in CD4+ T cells from older compared to younger donors and a higher number of LC3+ compartments among older donors. Since the overall amount of autophagosomes degraded was comparable between the two groups, we concluded that autophagosome biogenesis was reduced in the older group. Rather than a decline, our findings in healthy older donors point toward a compensatory enhancement of human CD4+ T cell autophagy with age, which may be a mechanism behind healthy aging.

Keywords:  CD4+ T cells; autophagy; healthy aging

DOI:  https://doi.org/10.1111/acel.70246
Neuro Oncol. 2025 Oct 17. pii: noaf236. [Epub ahead of print]

T cell immunity in glioma and potential implications for immunotherapy: a systematic review.

Rosa Luning, Pim J French, Wouter J F Vanbilloen, Lisa Dobber, Levi Van Hijfte, Raoull Hoogendijk, Martin J Van Den Bent, Reno Debets, Marjolein Geurts.

   BACKGROUND: T cell-based immunotherapies have had limited success in glioma thus far. Here, we evaluate the literature on abundance, spatial distribution and phenotypical characteristics of T cells in the tumor micro-environment (TME) of IDH-mutant and IDH-wildtype glioma, with the aim to understand how these measures relate to immunotherapy resistance and to aid the development of immunotherapies for glioma.
METHODS: Medline, Embase, Web of Science Core Collection, Google Scholar and the Cochrane Central Register of Controlled Trials were systematically searched up to May 6th, 2025. Out of 4,303 articles screened, 85 studies examining T cell immunity in human glioma were selected. We collected information about tumor subtype, grade, methods, T cell abundance, spatial distribution, phenotypes and prognostic significance.
RESULTS: T cells are present in the glioma TME, but at heterogeneous and generally low densities, especially in IDH-mutant glioma. T cell abundance increases with higher WHO grade and upon recurrence. T cells cluster around blood vessels, especially in IDH-mutant glioma. Glioma-infiltrating T cells largely display a late-differentiated phenotype (CD45RA-CCR7-C62L-), expressing markers that signify sustained antigen activation and exhaustion (PD-1, CTLA-4, TIM-3, LAG-3, CD39 and TIGIT). This phenotype coincides with decreased anti-tumor cytotoxicity and is spatially enriched in the myeloid-rich, hypoxic tumor core. Prognostic significance remains controversial.
CONCLUSIONS: T cells in glioma are scarce, generally fully differentiated and functionally inert. Understanding and reinvigorating the deficient T cell response will be essential for successful immunotherapies. Future research should incorporate functional and spatial immune profiling to optimize and personalize immunotherapeutic strategies for glioma patients.

Keywords:  Glioma; T cells; TME; immunotherapy; phenotype

DOI:  https://doi.org/10.1093/neuonc/noaf236
Liver Int. 2025 Nov;45(11): e70402

Metabolic Reprogramming and CD8+ T-Cell Exhaustion During Chronic HBV Infection.

Haohao Li, Weiwei Mu, Alison Zhao, Su Xiao, Chenxin Huo, Huajun Zhao, Hongchun Wang, Ronghui Li, Qiuju Han.

  HBV is an enveloped DNA virus that exclusively infects hepatocytes of humans and some non-human primates. During its viral life cycle, HBV and its structural components can directly regulate the metabolism of hepatocytes, which may reshape the liver immune microenvironment. CD8+ T-cells, well known as cytotoxic T lymphocytes for their antiviral immunity, can undergo metabolic reprogramming during chronic HBV infection. Increasing evidence demonstrates that metabolic reprogramming promotes T-cell exhaustion, which is a hallmark of HBV infection. Additionally, complicated metabolites (e.g., glucose, lipids, amino acids and nucleic acids) secreted from hepatocytes or T-cells contribute to the communication between these two cell types, which may facilitate HBV infection and hinder antiviral immune response. In recent years, supplementation of certain specific metabolic substrates or targeting metabolic enzyme genes has been reported to mitigate HBV replication and induce antiviral immune response, holding promise as effective strategies for curing chronic HBV infection. This review provides a thorough overview of recent advances in the metabolic characteristics of hepatocytes and T-cells during HBV infection, discusses the relationship between CD8+ T-cell exhaustion and metabolic reprogramming, and emphasises the therapeutic potential of metabolic approaches in the HBV clinical landscape.

Keywords:  CD8+ T‐cells; chronic hepatitis B; hepatocytes; immunometabolism; metabolic reprogramming

DOI:  https://doi.org/10.1111/liv.70402
Mol Cancer. 2025 Oct 16. 24(1): 261

Tumor-associated macrophages: untapped molecular targets to improve T cell-based immunotherapy.

Rui M L Coelho, Reno Debets, Dora Hammerl.

  T cell responses are generally curtailed by suppressive mechanisms within the tumor microenvironment (TME) that prevent T cell infiltration and function. Consequently, T cell-based therapies for solid tumors have yielded limited and often non-durable clinical responses. Tumors develop a hostile TME, where tumor-associated macrophages (TAMs) that initially support T cells are converted into immune suppressive TAMs that facilitate tumor evasion from T cell control. In fact, immune suppressive TAMs represent a dominant fraction of immune cells within the TME and their presence is associated with poor prognosis and resistance to immunotherapy. Often in close contact with effector T cells, TAMs directly suppress CD8+ T cells through mechanisms involving metabolic mediators, co-signaling receptors, their ligands and/or cytokines. Here, we revisit molecular interactions behind TAM-mediated suppression of T cell responses and address the potential targeting of such molecules and pathways to re-boost anti-tumor T cell immunity. This perspective, focusing on molecular interactions between TAM and T cells, may aid the improvement of T cell-based therapies for solid tumors.

Keywords:  AhR; B7-H4; Gal-3; Siglec-15; Siglec-9; T cell suppression; Tumor-associated macrophages; VISTA

DOI:  https://doi.org/10.1186/s12943-025-02481-w
Cell Biosci. 2025 Oct 14. 15(1): 139

Zinc finger protein Zfp335 is required for T cell homeostatic proliferation through regulating Lmnb1.

Biao Yang, Wenhua Li, Xin Wang, Ning Yuan, Yang Gao, Jiapeng Song, Jun Liu, Tianzhe Zhang, Haiyan Liu, Yuying Ren, Peng Chen, Xiaofeng Yang, Lei Lei, Xiaobo Zhou, Hui Zhang, Baojun Zhang.

   BACKGROUND: T cell homeostasis is crucial for maintaining T cell population size and upcoming protective immunity in the peripheral organs. However, it remains largely unknown about the intracellular molecules and pathways beyond IL-7R signaling. Zfp335, as a key transcription factor, is involved in the multiple-stage development of thymocytes, and effector and memory T cell differentiation during immune responses.
RESULTS: In current study, we found an upregulated expression of ZFP335 in both CD4+ and CD8+ T cells during peripheral homeostasis. In an adoptive transfer model, Zfp335-/- T cells failed to undergo homeostatic proliferation without survival defect. Consistently, deletion of Zfp335 impaired T cell proliferation in in vitro culture with IL-7. Furthermore, both RNA-Sequencing and qPCR analysis showed that Zfp335 significantly affected the expression of cell cycle-related genes. Mechanistically, Zfp335 directly binds to the promoter of Lmnb1 gene and regulates its transcription. Overexpression of Lmnb1 significantly rescued the impaired proliferation of Zfp335-/- T cells.
CONCLUSION: Our results reveal a previously unrecognized role of Zfp335 in maintaining T cell homeostasis within peripheral lymphoid tissues. Specifically, Zfp335 promotes the homeostatic proliferation of naïve T cells by directly modulating the expression of the Lmnb1 gene which ensuring the capacity of immune system.

Keywords:  Homeostasis; Periphery; Proliferation; T cell; Zfp335

DOI:  https://doi.org/10.1186/s13578-025-01483-x
J Immunother Cancer. 2025 Oct 13. pii: e012321. [Epub ahead of print]13(10):

Envirotune-CAR-T: a hypoxia-responsive and glutamine-enhanced CAR-T cell therapy for overcoming tumor microenvironment-mediated suppression.

Wenying Li, Jiannan Chen, Jiayi Li, Shuai Wang, Zhengliang Chen, Lianfeng Zhao, Yaoyao Zhao, Lili Gu, Jiaqi Liu, Yan Zhang, Xinhao Yang, Tianyu Chen, Zhigang Guo.

   BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapy has demonstrated remarkable success in hematologic malignancies; however, its efficacy in solid tumors remains limited. A major barrier is the immunosuppressive tumor microenvironment (TME), which is characterized by hypoxia and nutrient deprivation, leading to impaired CAR-T cell proliferation, persistence, and cytotoxic function. To address these barriers, we designed a dual-regulatory CAR-T strategy that integrates hypoxia-responsive control with metabolic enhancement to improve therapeutic efficacy in solid tumors.
METHODS: To overcome these barriers, we developed a next-generation CAR-T platform with dual adaptations targeting the metabolic and transcriptional constraints of the TME. Specifically, we engineered hypoxia-responsive regulatory elements derived from VEGF to drive sustained CAR expression under hypoxic conditions. Concurrently, we overexpressed the glutamine transporter SLC38A2 to enhance glutamine uptake and metabolic fitness in nutrient-deprived environments.
RESULTS: Compared with conventional CAR-T cells, our engineered CAR-T cells exhibited superior antitumor activity under hypoxia and nutrient stress, with enhanced proliferation, elevated memory phenotype, and reduced exhaustion markers. Mechanistically, quantitative PCR demonstrated upregulation of glutamine metabolic and glycolytic pathways, while Seahorse assays confirmed enhanced oxidative phosphorylation and glycolysis. SLC38A2 knockout reversed these enhancements, highlighting its role in sustaining CAR-T metabolic fitness.
CONCLUSION: Our findings establish SLC38A2 as a critical metabolic regulator that enhances CAR-T antitumor efficacy, providing a promising strategy to improve the durability and efficacy of CAR-T cell therapies in TME.

Keywords:  Chimeric antigen receptor - CAR; Immunotherapy; Memory; Solid tumor; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2025-012321
Nat Immunol. 2025 Oct 15.

The co-inhibitory receptor TIGIT promotes tissue-protective functions in T cells.

Camilla Panetti, Rahel Daetwyler, Anja Moncsek, Nikolaos Patikas, Andreas Agrafiotis, Adelynn Tang, Francesco Andreata, Valeria Fumagalli, Jean De Lima, Lifen Wen, Carolyn G King, Ajithkumar Vasanthakumar, Matteo Iannacone, Axel Kallies, Alexander Yermanos, Martin Hemberg, Nicole Joller.

The co-inhibitory receptor TIGIT suppresses excessive immune responses in autoimmune conditions while also restraining antitumor immunity. In viral infections, TIGIT alone does not affect viral control but has been shown to limit tissue pathology. However, the underlying mechanisms are incompletely understood. Here we found TIGIT+ T cells to express not only an immunoregulatory gene signature but also a tissue repair gene signature. Specifically, after viral infection, TIGIT directly drives expression of the tissue growth factor amphiregulin (Areg), which is strongly reduced in the absence of TIGIT. We identified regulatory T (Treg) cells, but not CD8+ T cells, as the critical T cell subset mediating these tissue-protective effects. In Treg cells, TIGIT engagement after T cell antigen receptor stimulation induces the transcription factor Blimp-1, which then promotes Areg production and tissue repair. Thus, we uncovered a nonclassical function of the co-inhibitory receptor TIGIT, wherein it not only limits immune pathology by suppressing the immune response but also actively fosters tissue regeneration by inducing the tissue growth factor Areg in T cells.

DOI: https://doi.org/10.1038/s41590-025-02300-w
Life Med. 2025 Oct;4(5): lnaf028

Fat talks first: how adipose tissue sets the pace of aging?

Juanhong Liu, Qinlei Huang, Feng Liu.

  Once viewed primarily as an energy reservoir, adipose tissue (AT) is now recognized as a key endocrinal organ in regulating systemic aging. With age, AT undergoes significant remodeling, marked by altered fat distribution, visceral fat expansion, impaired thermogenesis, and chronic low-grade inflammation, which disrupts metabolic and immune homeostasis. Emerging insights from single-cell and spatial transcriptomics highlight the critical roles of adipose progenitors, immune cells, and senescent cells in driving local dysfunction and systemic decline. Through inflammatory and metabolic signaling, dysfunctional AT actively contributes to age-related pathologies. This review explores how AT functions as both an early sensor and driver of aging and discusses therapeutic opportunities targeting adipose dysfunction to promote healthy aging.

Keywords:  adipose tissue; aging; cell senescent; inflammation; metabolic dysfunction

DOI:  https://doi.org/10.1093/lifemedi/lnaf028
Nat Rev Immunol. 2025 Oct 14.

Microenvironmental regulation of solid tumour resistance to CAR T cell therapy.

Zachary L Lamplugh, Nils Wellhausen, Carl H June, Yi Fan.

Chimeric antigen receptor (CAR) T cell therapy holds significant promise for the treatment of cancer; however, its efficacy in solid tumours is substantially hindered by the immunosuppressive tumour microenvironment (TME). Solid tumours can resist immunotherapy by impairing T cell trafficking, function and persistence. One of the initial obstacles that CAR T cells encounter is the abnormal tumour vasculature, which restricts efficient T cell infiltration, further compounded by a dense extracellular matrix. CAR T cells that do infiltrate the tumours are outnumbered by immunosuppressive cells such as regulatory T cells, myeloid-derived suppressor cells and tumour-associated macrophages. Additionally, tumour cells can contribute to CAR T cell resistance by upregulating immune checkpoint molecules, such as PDL1 and CTLA4, and engage in metabolic competition. In this Review, we discuss how cellular and non-cellular components of the TME impair CAR T cell therapy and consider potential strategies to improve CAR T cell therapies for solid tumours, either by reprogramming the TME or by engineering CAR T cells to resist the immunosuppressive effects of the TME.

DOI: https://doi.org/10.1038/s41577-025-01229-3
Cell Metab. 2025 Oct 16. pii: S1550-4131(25)00394-8. [Epub ahead of print]

Aged mice exhibit widespread metabolic changes but preserved major fluxes.

Connor S R Jankowski, Laith Z Samarah, Michael R MacArthur, Sarah J Mitchell, Daniel R Weilandt, Craig J Hunter, Xianfeng Zeng, Melanie R McReynolds, Joshua D Rabinowitz.

  Metabolic dysregulation is a hallmark of aging. Here, we investigate in mice age-induced metabolic alterations using metabolomics and stable isotope tracing. Circulating metabolite fluxes and serum and tissue concentrations were measured in young and old (20-30 months) C57BL/6J mice, with young obese (ob/ob) mice as a comparator. For major circulating metabolites, concentrations changed more with age than fluxes, and fluxes changed more with obesity than with aging. Specifically, glucose, lactate, 3-hydroxybutryate, and many amino acids (but notably not taurine) change significantly in concentration with age. Only glutamine circulatory flux does so. The fluxes of major circulating metabolites remain stable despite underlying metabolic changes. For example, lysine catabolism shifts from the saccharopine toward the pipecolic acid pathway, and both pipecolic acid concentration and flux increase with aging. Other less-abundant metabolites also show coherent, age-induced concentration and flux changes. Thus, while aging leads to widespread metabolic changes, major metabolic fluxes are largely preserved.

Keywords:  aging; fluxomics; glutamine; metabolic flux; metabolism; metabolomics; obesity; stable isotope tracing; systemic metabolism

DOI:  https://doi.org/10.1016/j.cmet.2025.09.009
Sci Rep. 2025 Oct 14. 15(1): 35861

Single-cell transcriptome analysis reveals the potential heterogeneous mechanism of CD8+ T cell immune dysfunction in thyroid cancer.

Qinling Zhang, Kaiyu Song, Chaolin Li, Xicheng Song, Jin Zhou.

  Anaplastic thyroid cancer (ATC) and papillary thyroid carcinoma (PTC) exhibit significant differences in clinical behavior and immune microenvironments, particularly concerning the mechanisms underlying CD8+ T cell dysfunction. However, these specific mechanisms have yet to be thorThe original blots and abbreviations are presented in Supplemeoughly investigated. The present study utilized single-cell RNA sequencing (scRNA-seq) data to conduct a comprehensive analysis of CD8+ T cells in the thyroid tissues of patients diagnosed with ATC and PTC. The results of the study indicate that CD8+ T cells in ATC display disruptions in energy supply and marked signs of exhaustion. Conversely, CD8+ T cells in PTC are more prone to maintaining a stable expression of immunosuppression-related membrane proteins through posttranslational modifications. This study highlights the distinct mechanisms of CD8+ T cell exhaustion in two types of thyroid cancer, offering valuable insights into the regulation of their immune microenvironments.

Keywords:  CD8+ t cell exhaustion; Mitochondrial dysfunction; Posttranslational modification; Single-cell RNA sequencing; Thyroid carcinoma

DOI:  https://doi.org/10.1038/s41598-025-19995-4
Cancer Immunol Res. 2025 Oct 13.

Single-cell clonal lineage tracing identifies the transcriptional program controlling the cell-fate decisions by neoantigen-specific CD8+ T cells.

Ying Luo, Taidou Hu, Chen Yao, Tuoqi Wu.

Neoantigen-specific T cells recognize tumor cells and are critical for cancer immunotherapies to be effective. However, the transcriptional program controlling the cell-fate decisions by neoantigen-specific T cells is incompletely understood. Here, using joint single-cell transcriptome and T-cell receptor (TCR) profiling, we mapped the clonal expansion and differentiation of neoantigen-specific CD8+ T cells in the tumor and draining lymph node in mouse prostate cancer. Neoantigen-specific CD8+ tumor-infiltrating lymphocytes (TILs) upregulated gene signatures of T-cell activation and exhaustion compared to those recognizing other tumor antigens. In the tumor-draining lymph node, we identified TCF1+TOX- TSCM, TCF1+TOX+ TPEX, and TCF1-TOX+ effector-like TEX subsets among neoantigen-specific CD8+ T cells. Divergent neoantigen-specific CD8+ T-cell clones with balanced distribution across multiple differentiation fates underwent significantly greater expansion compared to clones biased towards TEX, TPEX, or TSCM. The TPEX subset had greatest clonal diversity and likely represented the root of neoantigen-specific CD8+ T-cell differentiation, whereas highly clonally expanded effector-like TEX cells were positioned at the branch point where neoantigen-specific clones exited the lymph node and differentiated into TEX TILs. TSCM differentiation of neoantigen-specific CD8+ T-cell clones in the lymph node negatively correlated with exhaustion and clonal expansion of the same clones in the tumor. In addition, the gene signature of neoantigen-specific clones biased toward tumor infiltration relative to lymph-node residence predicted a poorer response to immune checkpoint inhibitors by cancer patients. In conclusion, we have identified a transcriptional program that controls the cell-fate choices by neoantigen-specific CD8+ T cells and correlates with clinical outcomes in cancer patients.

DOI: https://doi.org/10.1158/2326-6066.CIR-25-0203
Proc Natl Acad Sci U S A. 2025 Oct 21. 122(42): e2507154122

TCR signal-enhancing mutation alters lipid metabolism of thymocytes and impairs antitumor immunity of mature T cells.

Wenhua Liang, Yuge Liang, Mingzhu Yu, Chenshuang Ji, Feng Wang.

  The T cell receptor (TCR), a master regulator of adaptive immunity, serves as a molecular transducer that converts antigen recognition into precisely modulated intracellular signals, orchestrating both T cell development and effector functions. In this study, we leveraged a germline CD3εI173A mutation, a previously characterized alteration that amplifies TCR signaling through the disruption of inhibitory lipid interactions, to dissect how thymocyte-intrinsic TCR signaling amplification influences the fate of mature T cells. Remarkably, thymic double-positive cells in CD3εI173A mice with altered TCR repertoires demonstrated a significant downregulation of the phosphatidylserine decarboxylase homolog gene AC149090.1. This modulation triggered a comprehensive rewiring of lipid metabolic pathways, establishing a systemic compensatory mechanism to counterbalance excessive TCR signaling. These metabolic adaptations culminated in functionally compromised mature T cells, characterized by diminished activation potential, reduced proliferative capacity, and impaired antitumor efficacy in CD3εI173A mice. Our results underscore the critical role of thymic TCR signaling in T cell development for sustaining immune homeostasis and orchestrating mature T cell functionality, unveiling the lipid metabolic plasticity during thymocyte development that acts as a critical regulatory checkpoint for maintaining immune homeostasis.

Keywords:  CD3ε mutation; TCR signaling; antitumor immunity; gain-of-function; lipid metabolism

DOI:  https://doi.org/10.1073/pnas.2507154122
Front Immunol. 2025 ;16 1674163

Endoplasmic reticulum stress orchestrates tumor metabolism and immunity: new insights into immunometabolic therapeutics.

Zhang Fu, Mengyue Li, Huaixiang Zhou, Xin Zhong, Zhiqiang Zhang, Xianwen Meng, Youheng Jiang, Tao Wang, Ningning Li.

  Endoplasmic reticulum (ER) stress and its adaptive signaling network have emerged as central regulators of tumor progression, metabolic rewiring, and immune modulation. Within the nutrient-deprived and hypoxic tumor microenvironment, ER stress reprograms glucose, lipid, and amino acid metabolism, exerting context-dependent effects that influence both tumor cell viability and immune regulation. Concurrently, ER stress remodels the metabolic fitness and functional states of immune cells, influencing T cell exhaustion, macrophage polarization, and dendritic cell maturation. Emerging evidence indicates that tumor- and immune-cell-derived metabolites (e.g., lactate, fatty acids, and tryptophan derivatives) exert both metabolic and immunomodulatory functions, thereby shaping a dynamic "ER stress-metabolism-immunity" axis that underlies cancer heterogeneity, immune evasion, and therapeutic resistance. In this review, we synthesize recent advances delineating how canonical ER stress pathways intersect with immunometabolic reprogramming across tumor and immune compartments, and we discuss how this integrated axis reshapes the tumor immune microenvironment (TIME). Targeting this integrated axis may unveil new strategies to overcome metabolic vulnerabilities and enhance the efficacy of immunotherapy.

Keywords:  endoplasmic reticulum stress; immunometabolism; metabolic reprogramming; tumor immune microenvironment; unfolded protein response

DOI:  https://doi.org/10.3389/fimmu.2025.1674163
iScience. 2025 Oct 17. 28(10): 113600

Identification of antigen-specific functional CD8+ T cells using an optofluidic system independent of epitope information.

Wei Zhang, Yu Liu, Hongxiang Zeng, Xuejiao Liao, Juanjuan Zhao, Xian Tang, Zheng Zhang.

  Most studies detect and isolate antigen-specific CD8+ T cells solely by measuring T cell receptor (TCR) binding affinity to peptide-major histocompatibility complexes (p-MHCs) without considering T cell function. Here, we present a function-based strategy to screen antigen-specific CD8+ T cells using the Lightning optofluidic platform, named MicroFAST (microfluidic function-based screening of antigen-specific single T lymphocyte) fitting for limited sample volume. We validated this method by using it to isolate human cytomegalovirus (HCMV)-specific CD8+ T cells targeting a known HLA-A∗02:01-restricted epitope. We finally applied this method to identify several SARS-CoV-2-specific TCRs, which were characterized by recognizing HLA-B∗35:01-restricted TPS epitope (TPSGTWLTY), demonstrating the utility of our system. TCR binding affinity did not associate with its functionality. Collectively, we developed a workflow of isolating antigen-specific functional CD8+ T cells with or without a prior knowledge of peptide-MHC specificities, which will facilitate the development of engineered TCR-T therapies and T cell-based vaccines.

Keywords:  Immunological methods; Immunology

DOI:  https://doi.org/10.1016/j.isci.2025.113600
Immunity. 2025 Oct 14. pii: S1074-7613(25)00428-5. [Epub ahead of print]58(10): 2364-2366

Resident memory T cells call the shots in tissue immunity.

Sigrun Stulz, Georg Gasteiger.

Vaccines that induce immunity in tissues are urgently needed. In this issue of Immunity, Joag et al. demonstrate that systemic vaccination of primates induces tissue-resident CD8+ T cells in numerous organs that can activate antiviral responses by stromal, parenchymal, and immune cells.

DOI: https://doi.org/10.1016/j.immuni.2025.09.017
J Transl Med. 2025 Oct 17. 23(1): 1127

Targeting PURPL RNA enabled rejuvenation of senescence cells via epigenetic reprogramming.

Jie Wang, Xiao Yang, Xinyu Su, Wenkai Yi, Wei Sun, Jie Wei, Yong-Qiang Ning, Jian Yan.

  Cellular senescence is a fundamental driver of ageing and age-related diseases, characterized by irreversible growth arrest and profound epigenetic alterations. While long non-coding RNAs (lncRNAs) have emerged as key regulators of senescence, their potential for senescent cell rejuvenation remains unexplored. Here, we identify the ageing-associated lncRNA PURPL as an epigenetic regulator that controls cellular rejuvenation through H3K9me3-mediated transcriptional silencing. CRISPRi-mediated PURPL depletion produces striking rejuvenation effects, resulting in restored youthful cell morphology, as well as suppression of senescence markers such as p21 and SA-β-gal. Conversely, PURPL overexpression accelerates cellular senescence, recapitulating the transcriptional and phenotypic hallmarks of ageing. Mechanistically, nuclear-localized PURPL regulates H3K9me3 deposition at 411 genomic loci including SERPINE1 (PAI-1) and EGR1, which are key senescence drivers. PURPL-mediated H3K9me3 loss at these loci derepresses their transcription, establishing a pro-senescence gene expression program. These findings reveal that PURPL is an epigenetic modulator of senescence and highlight its potential as a therapeutic target for age-related pathologies.

Keywords:  Cellular senescence; H3K9me3; Histone modification; Long non-coding RNA; PURPL

DOI:  https://doi.org/10.1186/s12967-025-07208-5
Cytotechnology. 2025 Oct;77(5): 185

Sargentodoxa cuneata suppresses lung adenocarcinoma progression by enhancing cytotoxic CD8+ T activity through the ACY1/ARG2 interaction.

Jun Xu, Laishun Yuan, Haohao Wu, Hui Xu, Bo Yang, Fen Hu.

  Cytotoxic CD8+ T lymphocytes play a pivotal role in anti-tumor immunity by eliminating cancer cells. Sargentodoxa cuneata (Sar) has demonstrated anti-cancer potential. This study investigated the therapeutic potential of Sar in lung adenocarcinoma (LUAD) through its modulation of CD8+ T cell tumoricidal capacity. CD8+ T cells were isolated and co-cultured with treated HCC2935 and H1975 LUAD cell lines. The influences on LUAD cells were assessed by detecting cell viability and apoptosis. The impacts on CD8+ T cells were evaluated by measuring cell cytotoxic activity and IFN-γ and TNF-α secretion. The aminoacylase-1 (ACY1)/arginase-2 (ARG2) interaction was predicted by molecular docking and confirmed by GST pull-down and Co-IP assays. Animal xenograft experiments were used to analyze the therapeutic potential of Sar in vivo. ACY1 and ARG2 were upregulated and positively associated with PD-L1 expression in LUAD samples. Mechanistically, ACY1 physically interacted with ARG2 in LUAD cells. ACY1 inhibited apoptosis in LUAD cells and attenuated cytotoxic activity of CD8+ T lymphocytes via ARG2. Moreover, Sar induced LUAD cell apoptosis and enhanced CD8+ T cell cytotoxicity by downregulating ACY1 in vitro. Sar attenuated xenograft tumor development through ACY1 downregulation in vivo. Our study establishes that Sar emerges as a promising therapeutic agent in LUAD by enhancing CD8+ T tumoricidal capacity through targeting the ACY1/ARG2 co-regulatory axis.
Graphical abstract: Sargentodoxa cuneata (Sar) reduces ACY1 expression to disrupt the ACY1/ARG2 interaction and thus downregulates PD-L1, consequently inducing LUAD cell apoptosis and enhancing CD8+ T cell cytotoxicity.
Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-025-00849-w.

Keywords:  Aminoacylase-1; Arginase-2; CD8+ T lymphocytes; Lung adenocarcinoma; Sargentodoxa cuneata

DOI:  https://doi.org/10.1007/s10616-025-00849-w
Sci Adv. 2025 Oct 17. 11(42): eadw3571

Enhanced FOS expression improves tumor clearance and resists exhaustion in NR4A3-deficient CAR T cells under chronic antigen exposure.

Peidi Yin, Jigui Yang, Yiyang Jiang, Linhong Han, Tianchen Xiong, Haofei Liu, Yiliang Fang, Wenchen Ruan, Jiayang Wu, Longjuan Chen, Leyong Tan, Yonglin Zuo, Xin Wu, Fangyuan Mao, Rui Huang, Xindong Liu, Xiu-Wu Bian.

The dysfunction of chimeric antigen receptor (CAR) T cells in the tumor microenvironment is a major obstacle to their therapeutic efficacy against solid tumors. Through single-cell RNA sequencing analysis of tumor-infiltrating T cells from patients with glioma, NR4A family genes were identified as closely associated with T cell exhaustion and were coexpressed with dysfunctional genes HAVCR2 and TIGIT. Notably, CAR T cells with NR4A3 knockdown exhibited enhanced cytotoxic activity against tumors, leading to improved tumor clearance and prolonged survival in vivo. However, the promoted antiexhausted phenotype diminished with prolonged tumor burden. This decline in T cell function correlates with the compensatory down-regulation of FOS induced by chronic antigen exposure following NR4A3 knockdown. Overexpressing FOS alongside NR4A3 knockdown robustly boosted the antitumor responses of CAR T cells by skewing their phenotypes and transcriptional profiles away from exhaustion and toward increased effector function. These findings offer a promising strategy for the clinical modification of CAR T cell therapy.

DOI: https://doi.org/10.1126/sciadv.adw3571
Biochim Biophys Acta Rev Cancer. 2025 Oct 10. pii: S0304-419X(25)00213-6. [Epub ahead of print]1880(6): 189471

Mitochondrial dynamics and metabolic attributes regulate function of natural killer cell and infiltration in tumor microenvironment modulating disease progression.

Sayak Ghosh, Rittick Dutta, Devyani Goswami, Debapriya Ghatak, Rudranil De.

  Mitochondria in natural killer (NK) cells orchestrate a dynamic interplay between energy production and immune regulation, placing them at the forefront of oncogenesis and tumor microenvironment (TME) infiltration. This review unravels the intricate disruptions in mitochondrial dynamics-fission, fusion, and biogenesis-that hypoxia imposes within the TME, culminating in impaired NK cell functionality. Hypoxia-driven mitochondrial fragmentation, mediated by HIF-1α and mTOR-Drp1 signaling, cripples NK cell cytotoxicity, proliferation, and maturation, while elevated ROS levels and metabolic reprogramming bolster tumor immune evasion. The metabolic landscape of the TME adds another layer of complexity, with amino acid depletion significantly hindering NK cell performance. Arginine and leucine deficiencies suppress proliferation and mTOR activation, whereas disrupted glutamine metabolism impairs cMyc-driven metabolic adaptation. Additionally, immunosuppressive catabolites like nitric oxide and L-kynurenine exacerbate NK cell dysfunction by curbing cytokine production and receptor expression. Targeting these metabolic vulnerabilities offers a promising strategy; specifically, interventions aimed at amino acid pathways could simultaneously restrict nutrient availability within the tumor microenvironment and preserve NK cell functionalities. Emerging strategies spotlight the potential of NK cells to induce autophagic death in hypoxic cancer cells, a mechanism that could restore their cytotoxic potential. Furthermore, immune checkpoint pathways, such as PD-1 and CTLA-4, amplify mitochondrial dysfunction, underscoring their therapeutic significance. By addressing hypoxia, metabolic dysregulation, and mitochondrial reprogramming, this review illuminates actionable strategies to reinvigorate NK cell-mediated antitumor responses and pave the way for transformative cancer therapies.

Keywords:  Cancer; Glutamine; Hypoxia; Immunometabolism; Mitochondria; Natural killer (NK) cells

DOI:  https://doi.org/10.1016/j.bbcan.2025.189471