bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–09–21
forty-two papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Lymph nodes fuel KLF2-dependent effector CD8+ T cell differentiation during chronic infection and checkpoint blockade.
  2. Mitochondrial Activity Regulates Human T Helper 17 Differentiation and Function.
  3. Leveraging innate immune signals in CD8+ T cells to boost antitumor immunity.
  4. Decoding immunometabolism with next-generation tools: lessons from dendritic cells and T cells.
  5. Integrin CD103 expression in naive CD8+ T cells promotes cytokine-driven acquisition of memory phenotype and effector function.
  6. PHD2 Deletion in CD8+ T Cells Worsens TAC-Induced Cardiac Inflammation, Heart Failure, and Pulmonary Remodeling.
  7. Genetic and epigenetic screens in primary human T cells link candidate causal autoimmune variants to T cell networks.
  8. Metabolic hallmarks of type 2 diabetes compromise T cell function.
  9. Mitochondrial lipid metabolism in tumor immunosurveillance and evasion.
  10. Cellular cholesterol metabolism rewiring through SREBP2-LXR-mTOR signaling convergence orchestrates T cell fate and keratinocyte apoptosis in oral lichen planus.
  11. Label-free metabolic imaging monitors the fitness of chimeric antigen receptor T cells.
  12. The endogenous T cell landscape is reshaped by CAR-T cell therapy and predicts treatment response in multiple myeloma.
  13. Exploring the effects of exercise on T cell function and metabolism in cancer: a scoping review protocol.
  14. USP14-mediated metabolic competition impairs CD8+ T cell immunosurveillance in hepatocellular carcinoma.
  15. Metabolic regulation in the senescence process of stem cells.
  16. Lactate metabolic checkpoint in immuno-oncology: mechanisms and therapeutic implications.
  17. Harnessing Metabolism to Combat Neurodegeneration: Strategies for Reversing Age-Related Cognitive Decline.
  18. The emerging roles of the urea cycle in tumor microenvironment and therapies.
  19. Effects of CRISPR-Cas9-mediated FOXP3 knockout on CAR T cell potency.
  20. Microbiota-derived butyrate potentiates MSLN CAR-T cell therapy by metabolic reprogramming and extracellular matrix remodeling.
  21. Optimizing mitochondria function in immune cells: implications for cancer immunotherapy.
  22. Reprogramming Factors Activate a Non-Canonical Oxidative Resilience Pathway That Can Rejuvenate RPEs and Restore Vision.
  23. Activation of T cell-intrinsic p53 by acetylation elicits antitumor immunity to boost cancer immunotherapy.
  24. A thymus-independent artificial organoid system supports complete thymopoiesis from Rhesus macaque-derived hematopoietic stem and progenitor cells.
  25. Advancing biological understanding of cellular senescence with computational multiomics.
  26. Mitoepigenetic Targeting of Age-Related Dysfunction: Mechanisms, Therapeutic Avenues, and Transgenerational Implications.
  27. Step-by-step: the CD8 T cell journey in leishmaniasis.
  28. Tumor Genotype Dictates Mitochondrial and Immune Vulnerabilities in Liver Cancer.
  29. CAR T cell persistence in cancer.
  30. Editorial: Mitochondria in metabolic reprogramming and immune activation: the key gene and therapeutic target.
  31. Intrinsic T cell glutaminolysis promotes autoimmunity in lupus-prone mice.
  32. Reprogramming glutamine metabolism enhances BCMA-CART cell fitness and therapeutic efficacy in multiple myeloma.
  33. TNFR2 is Expressed by a Discrete Subset of Epidermal γδ T Cells with an IL-17 Gene Signature during Psoriasis.
  34. Mitochondrial-activity-driven hematopoietic stem cell fate and lineage choice is first established in the aorta-gonad-mesonephros.
  35. Exploratory trajectory inference reveals convergent lineages for CD8 T cells in chronic LCMV infection.
  36. The gut microbiota directs vitamin A flux to regulate intestinal T cell development.
  37. T cell-intrinsic cGAS-CTCF regulation maintains regulatory T cell development and function.
  38. Dual checkpoint blockade of glioblastoma with Anti-PD-1 and Anti-LAG-3 promotes expansion of tumor-reactive T cell clones along a unique pathway of differentiation.
  39. Intrathecally expanded GZMK+/GZMH+ CD8 T cells targeting EBV antigens may reduce severity of Multiple Sclerosis.
  40. Spermidine potentiates anti-tumor immune responses and immunotherapy sensitivity in breast cancer.
  41. Current status of chimeric antigen receptor T cell therapy and its exhaustion mechanism.
  42. Metabolic Reprogramming of Cancer Cells and Therapeutics Targeting Cancer Metabolism.
  1. Nat Immunol. 2025 Sep 15.
    Lymph nodes fuel KLF2-dependent effector CD8+ T cell differentiation during chronic infection and checkpoint blockade.
    Carlson Tsui, Leonie Heyden, Lifen Wen, Catarina Gago da Graça, Nikita Potemkin, Aleksej Frolov, Daniel Rawlinson, Lei Qin, Verena C Wimmer, Marjan Hadian-Jazi, Darya Malko, Chun-Hsi Su, Sining Li, Kayla R Wilson, Helena Horvatic, Sharanya K Wijesinghe, Marcela L Moreira, Lachlan Dryburgh, Dominik Schienstock, Lisa Rausch, Daniel T Utzschneider, Cornelia Halin, Scott N Mueller, Marc D Beyer, Sammy Bedoui, Zeinab Abdullah, Jan Schröder, Axel Kallies.
      Exhausted CD8+ T (TEX) cell responses are maintained by precursors of exhausted T (TPEX) cells that possess high self-renewal and developmental potential. TPEX cells also drive the proliferative burst of effector T cells upon therapeutic immune checkpoint blockade (ICB). However, the spatial context and signals that regulate their differentiation and function are not well defined. Here we identify developmental and functional compartmentalization of TPEX and TEX cells across secondary lymphoid organs during chronic infection. We show that stem-like CD62L+ TPEX and effector-like CX3CR1+ TEX cells constitute a distinct developmental lineage that is promoted by the lymph node (LN) microenvironment and dependent on the transcription factor KLF2. LNs act as a niche in which migratory dendritic cells provide antigen and costimulatory signals to maintain the proliferative fitness of CD62L+ TPEX cells and generation of CX3CR1+ TEX cells. Moreover, LNs exclusively drive the proliferative burst and systemic dissemination of CX3CR1+ TEX cells during ICB. Thus, our findings identify a unique role for LNs in the maintenance of T cell differentiation and function during systemic chronic infection and ICB therapy.
    DOI:  https://doi.org/10.1038/s41590-025-02276-7
  2. Immunology. 2025 Sep 17.
    Mitochondrial Activity Regulates Human T Helper 17 Differentiation and Function.
    Xinlai Chen, Theodoros Ioannis Papadimitriou, Anne H G van Essen, Britt van Brunschot, Monique M Helsen, Annet Sloetjes, Elly L Vitters, Werner J H Koopman, Peter M van der Kraan, Arjan P M van Caam, Marije I Koenders.
      Immunometabolism plays a pivotal role in T cell fate decisions, yet its specific contribution to human Th17 differentiation remains incompletely understood. Th17 cells, a subset of CD4+ T cells, are central to autoimmune pathogenesis through their secretion of pro-inflammatory cytokines. Elucidating the metabolic drivers of Th17 differentiation may reveal novel therapeutic targets. We investigated the role of mitochondrial activity in Th17 differentiation using an in vitro model with naïve human CD4+ T cells. Single-cell metabolic profiling and functional assays were used to characterise metabolic changes during differentiation. Th17 cells exhibited a hyperpolarised mitochondrial membrane potential (ΔΨ) compared to non-Th17 cells. Hyperpolarised ΔΨ cells displayed increased metabolic activity and enhanced differentiation capacity. Metabolic profiling at 48 h revealed an early reliance on glycolysis, followed by a shift toward increased dependence on oxidative phosphorylation (OXPHOS) by 96 h. Gene expression analysis indicated early upregulation of TEFM, a mitochondrial transcription regulator, at 48 h. By 96 h, ΔΨ hyperpolarised cells exhibited a downregulation of DRP1 and MFN2, genes responsible for mitochondrial fission and fusion. Functionally, ΔΨ hyperpolarised cells expressed elevated activation markers (CD69, CD25) but also showed increased exhaustion markers (TIGIT, PD-1), indicating a link between high metabolic activity and exhaustion. Additionally, these cells triggered weaker NF-κB and AP-1 signalling and secreted lower levels of effector molecules (IFN-γ, Granzyme B) than ΔΨ depolarised cells. In conclusion, mitochondrial activity critically shapes Th17 differentiation. Although hyperpolarised ΔΨ cells exhibit greater activation, they are more prone to exhaustion and reduced effector function. These findings offer insights into Th17 metabolic regulation and its therapeutic potential in autoimmune diseases.
    Keywords:  T cell exhaustion; T cell metabolism; Th17 cells; Th17 differentiation; mitochondrial activity
    DOI:  https://doi.org/10.1111/imm.70037
  3. Front Immunol. 2025 ;16 1617773
    Leveraging innate immune signals in CD8+ T cells to boost antitumor immunity.
    Gabriella K Albert, Phoebe Cao, Eduardo Davila.
      Pattern recognition receptors (PRRs), traditionally characterized in innate immune cells, are emerging as critical modulators of T cell function. Toll-like receptors (TLRs), STING, RIG-I-like receptors (RLRs), and natural killer receptors (NKRs) are expressed by CD8+ T cells, where they influence various cellular responses. Primarily serving as noncanonical costimulatory signals, TLRs can modulate T cell activation, differentiation, metabolic fitness, and memory formation. RLRs and STING can promote T cell expansion and cytokine production. Both activating and inhibitory NKRs can also alter T cell cytotoxicity and differentiation. As demonstrated in recent advancements, the capacity of these signaling cascades to enhance T cell responses offers promising therapeutic opportunities in cancer. Clinical strategies are being developed to selectively harness each of these pathways, such as TLR and STING agonists to bolster antitumor responses, and NKR-based approaches to amplify cytotoxic function. Additionally, adoptive T cell therapies, such as chimeric antigen receptor (CAR)-T cells, are incorporating these innate signaling components to overcome tumor-mediated immunosuppression, enhance functional longevity, and improve therapeutic efficacy. This review discusses the progress made to characterize the role of T cell intrinsic PRR activity in shaping T cell functions and highlights recent advancements in that leverage innate receptor signaling to enhance the efficacy of cancer immunotherapies.
    Keywords:  T cell immunotherapy; antitumor immunity; innate receptor signaling; innate-like stimulation; pattern recognition receptors
    DOI:  https://doi.org/10.3389/fimmu.2025.1617773
  4. EMBO J. 2025 Sep 16.
    Decoding immunometabolism with next-generation tools: lessons from dendritic cells and T cells.
    Yi-Hao Wang, Limei Wang, Ping-Chih Ho.
      Cellular metabolism plays a pivotal role in regulating the effector functions and fate decisions of immune cells, shaping immune responses in homeostasis and disease. Metabolic pathways also serve as critical signaling hubs governing immune cell behavior. Deregulated metabolic pathways contribute to immune dysfunction, fueling disease progression and creating challenges for therapeutic interventions. The recent development of advanced technologies to delineate immunometabolic regulation has revolutionized our understanding of immune cell biology. These tools, ranging from quantitative single-cell metabolomics to in vivo spatial tissue profiling and DC-based metabolic therapy, have shifted the focus from broad nutrient pathways to a detailed exploration of metabolic reprogramming within disease microenvironments, revealing how metabolic changes drive immune cell activation, differentiation, and effector responses. The integration of immunometabolic insights into clinical practice holds strong potential for advancing precision medicine and developing targeted therapies that restore immune balance in pathological conditions. Here, we summarize emerging cutting-edge technologies related to immunometabolism and critically reflect on their current limitations. Finally, we discuss potential needs for developing novel methods that can uncover the intricate interplay between metabolism and immune cell function.
    Keywords:  Dendritic Cells; Immunometabolism; Metabolic Reprogramming; T Cells; Technological Advances
    DOI:  https://doi.org/10.1038/s44318-025-00569-z
  5. Immunity. 2025 Sep 15. pii: S1074-7613(25)00377-2. [Epub ahead of print]
    Integrin CD103 expression in naive CD8+ T cells promotes cytokine-driven acquisition of memory phenotype and effector function.
    Can Li, Davinna L Ligons, Dominic Lanasa, Hilary R Keller, Megan A Luckey, Brian Capaldo, Daoud Meerzaman, Joo-Young Park, Jung-Hyun Park.
      Integrin CD103 binds to E-cadherin, a cell adhesion molecule predominantly expressed on epithelial cells, thus mediating the tissue residency of CD103+ T cells in barrier sites. Importantly, circulating naive CD8+ T cells also express large amounts of CD103, but whether CD103 contributes to CD8+ T cell immunity beyond its role in cell adhesion is unclear. Here, we report that CD103 expression in naive CD8+ T cells facilitates their engagement with E-cadherin-expressing cells, promoting their acquisition of memory phenotype and effector function. Notably, dendritic cell (DC) subsets expressing E-cadherin and producing type I interferons and interleukin-12 (IL-12) were responsible for this process. As a corollary, the DC-specific loss of E-cadherin resulted in diminished effector CD8+ T cell differentiation and increased tumor susceptibility, while the forced expression of CD103 enhanced the effector functions and anti-tumor activity of CD8+ T cells, revealing a regulatory role for CD103 in cytotoxic T cell immunity.
    Keywords:  E-cadherin; IFN-β; IL-12; IL-15; dendritic cells
    DOI:  https://doi.org/10.1016/j.immuni.2025.08.014
  6. Hypertension. 2025 Sep 17.
    PHD2 Deletion in CD8+ T Cells Worsens TAC-Induced Cardiac Inflammation, Heart Failure, and Pulmonary Remodeling.
    Lihong Pan, Xiaochen He, Rui Xu, Umesh Bhattarai, Dongzhi Wang, Hao Wang, Ziru Niu, Heng Zeng, John Clemmer, Josh Speed, Jian-Xiong Chen, Yingjie Chen.
       BACKGROUND: Cardiac inflammation is a key driver of cardiac fibrosis and heart failure. Cytotoxic CD8⁺ T cells play important roles in modulating inflammatory responses, especially during infections and autoimmune diseases. HIFs (hypoxia-inducible factors) regulate CD8⁺ T cell function and cardiac remodeling. However, the role of HIF in CD8⁺ T cells during heart failure development remains unclear.
    METHODS: We generated CD8⁺ T cell-specific PHD2 (prolyl hydroxylase domain protein 2)-deficient mice (PHD2CKO), in which HIF bioavailability is increased due to the loss of PHD2. PHD2CKO and wild-type littermates were subjected to pressure overload via transverse aortic constriction. Cardiac function, inflammation, and CD8⁺ T cell responses were assessed. CD8⁺ T cell metabolism was analyzed using Seahorse assays to measure extracellular acidification rate and oxygen consumption rate. HIF1α and HIF2α protein levels were measured by Western blotting.
    RESULTS: Under baseline conditions, PHD2 deletion in CD8⁺ T cells had no effect on heart function or effector molecule expression. Following transverse aortic constriction, PHD2CKO mice showed exacerbated cardiopulmonary inflammation, fibrosis, and dysfunction. These effects were associated with enhanced CD8⁺ T cell activation and cytokine production. In vitro, PHD2-deficient CD8⁺ T cells exhibited increased glycolysis (extracellular acidification rate), reduced oxidative phosphorylation (oxygen consumption rate), and elevated HIF1α-but not HIF2α-levels. Pharmacological inhibition of HIF1α, but not HIF2α, reversed these metabolic and functional changes.
    CONCLUSIONS: PHD2 deletion in CD8⁺ T cells aggravates cardiopulmonary remodeling after pressure overload by enhancing CD8⁺ T cell activation and cytokine release via a HIF1α-dependent mechanism.
    Keywords:  animals; cytokines; fibrosis; heart failure; hypoxia
    DOI:  https://doi.org/10.1161/HYPERTENSIONAHA.125.25284
  7. Nat Genet. 2025 Sep 18.
    Genetic and epigenetic screens in primary human T cells link candidate causal autoimmune variants to T cell networks.
    Ching-Huang Ho, Maxwell A Dippel, Meghan S McQuade, LeAnn P Nguyen, Arpit Mishra, Stephan Pribitzer, Samantha Hardy, Harshpreet Chandok, Florence M Chardon, Troy A McDiarmid, Hannah A DeBerg, Jane H Buckner, Jay Shendure, Carl G de Boer, Michael H Guo, Ryan Tewhey, John P Ray.
      Genetic variants associated with autoimmune diseases are highly enriched within putative cis-regulatory regions of CD4+ T cells, suggesting that they could alter disease risk through changes in gene regulation. However, very few genetic variants have been shown to affect T cell gene expression or function. Here we tested >18,000 autoimmune disease-associated variants for allele-specific effects on expression using massively parallel reporter assays in primary human CD4+ T cells. We find 545 variants that modulate expression in an allele-specific manner (emVars). Primary T cell emVars greatly enrich for likely causal variants, are mediated by common upstream pathways and their putative target genes are highly enriched within a lymphocyte activation network. Using bulk and single-cell CRISPR-interference screens, we confirm that emVar-containing T cell cis-regulatory elements modulate both known and previously unappreciated target genes that regulate T cell proliferation, providing plausible mechanisms by which these variants alter autoimmune disease risk.
    DOI:  https://doi.org/10.1038/s41588-025-02301-3
  8. Trends Endocrinol Metab. 2025 Sep 12. pii: S1043-2760(25)00174-2. [Epub ahead of print]
    Metabolic hallmarks of type 2 diabetes compromise T cell function.
    Yuteng Liang, Weixin Chen, Qier Gao, Kathryn Choon-Beng Tan, Chi-Ho Lee, Guang Sheng Ling.
      Type 2 diabetes (T2D) manifests as profound systemic metabolic dysregulation. Mounting evidence indicates T2D significantly impairs T cell immunity, compromising both protective immune responses and immune homeostasis. This dysfunction stems from the multitude roles of metabolites in T cell biology: energy substrates, signaling molecules, and epigenetic regulators. In this review, we synthesize current evidence on how the metabolic hallmarks of T2D (hyperglycemia, hyperinsulinemia, and dyslipidemia) reprogram T cell metabolism and their functionalities. Notably, most patients with T2D receive combination antidiabetic therapies which not only correct systemic metabolism but also exert direct immunomodulatory effects on T cells. Unraveling the interplay between disease-driven metabolic perturbations and pharmacologically induced immunomodulation is essential to advance therapeutic strategies that restore immune competence while preserving immunoregulatory balance.
    Keywords:  T cells; immunometabolism; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.tem.2025.08.005
  9. Trends Immunol. 2025 Sep 16. pii: S1471-4906(25)00215-7. [Epub ahead of print]
    Mitochondrial lipid metabolism in tumor immunosurveillance and evasion.
    Ana Belén Plata-Gómez, Weixin Chen, Ping-Chih Ho, Guang Sheng Ling.
      Mitochondrial lipid metabolism plays a pivotal role in tumor immunosurveillance and immune evasion. This review explores how mitochondrial regulation shapes immune cell metabolism within the tumor microenvironment (TME), focusing on the antitumor effects of the mitochondrial-fueled immune response and the detrimental impact of impaired mitochondrial function on immune cell cytotoxicity. Although current studies support this dual role, critical gaps remain, including how immune cells adapt differently to the lipid-rich TME, and how therapies can target lipid metabolism without harming immune memory. By synthesizing current findings and highlighting these uncertainties, this review highlights mitochondrial lipid metabolism as a promising therapeutic axis in cancer immunotherapy.
    Keywords:  immunometabolism; lipid metabolism; mitochondria; tumor metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.it.2025.08.005
  10. Int Immunopharmacol. 2025 Sep 15. pii: S1567-5769(25)01448-1. [Epub ahead of print]166 115457
    Cellular cholesterol metabolism rewiring through SREBP2-LXR-mTOR signaling convergence orchestrates T cell fate and keratinocyte apoptosis in oral lichen planus.
    Qin Jiang, Yu-Xi Tang, Gang Zhou.
       BACKGROUND: Oral lichen planus (OLP) is a chronic inflammatory disease with unknown etiology and lack of curative treatment, characterized by T-cell infiltration and basal keratinocyte degeneration. As an emerging regulatory switch in immune inflammation, cholesterol metabolism profoundly influenced the biological fate and functions of T cells. However, it remains completely unknown whether T cell cholesterol metabolism contributes to the pathogenesis of OLP.
    METHODS: Single-cell RNA sequencing data screening and multi-platform validation (Immunohistochemistry, immunofluorescence, flow cytometry, PCR, co-immunoprecipitation) were performed to profile cholesterol metabolism dysregulation in OLP T cells, focusing on cholesterol accumulation, SREBP2-LXR imbalance and disease severity correlations. Functional validation employed cholesterol-modulated (fatostatin, GW3965, exogenous cholesterol) OLP plasma-pretreated Jurkat T cells and primary OLP T cells in keratinocyte co-cultures, with pathway analysis of STAT3, mTOR, STING and mTOR-SREBP2 crosstalk.
    RESULTS: Local OLP T cells exhibited elevated cholesterol scores (erosive > non-erosive), with cholesterol-high clusters showing enhanced cell cycle, leukocyte transendothelial migration, Th17 cell differentiation, and STAT3/mTOR/STING pathways. OLP lesions, local OLP T cells and peripheral OLP T cells exhibited accumulated cholesterol and SREBP2-LXR axis imbalance characterized by upregulated SREBP2/LXRα/LXRβ with hyperactive SREBP2, impaired LXR activity and attenuated LXRβ-RXRα interaction. LXRβ positively correlated with disease severity, and SREBP2 levels peaked in atrophic OLP. Cholesterol accumulation in OLP plasma-pretreated Jurkat T cells enhanced proliferation, cell cycle progression, migration, pro-keratinocyte apoptotic capacity and Th1/Th17 polarization but suppressed apoptosis, though excess cholesterol tended to impair the survival and pro-keratinocyte apoptosis ability. OLP CD4+ T cells exhibited greater cholesterol dependence than CD8+ T cells for proliferation and migration. Mechanistically, cholesterol activated mTOR while tending to suppress STING in OLP T cells. Bidirectional mTOR-SREBP2 crosstalk was observed, wherein mTOR activated SREBP2 whereas SREBP2 reciprocally inhibited mTOR, and the dual-pathway inhibition synergistically promoted OLP T cell apoptosis and suppressed proliferation.
    CONCLUSION: Cholesterol accumulation caused by OLP severity-associated SREBP2-LXR axis abnormalities promoted the immunobiological characteristics, pro-apoptotic effects on keratinocytes and mTOR pathway activation of OLP T cells, and the combined inhibition of mTOR-SREBP2 crosstalk alleviated T-cell responses in OLP.
    Keywords:  Cholesterol; Keratinocyte; Oral lichen planus; SREBP2-LXR axis; T cell; mTOR
    DOI:  https://doi.org/10.1016/j.intimp.2025.115457
  11. Nat Biomed Eng. 2025 Sep 16.
    Label-free metabolic imaging monitors the fitness of chimeric antigen receptor T cells.
    Dan L Pham, Dan Cappabianca, Matthew H Forsberg, Cole Weaver, Katherine P Mueller, Anna Tommasi, Jolanta Vidugiriene, Anthony Lauer, Kayla Sylvester, Jorgo Lika, Madison Bugel, Jing Fan, Christian M Capitini, Krishanu Saha, Melissa C Skala.
      Chimeric antigen receptor (CAR) T cell therapy for solid tumours is challenging because of the immunosuppressive tumour microenvironment and a complex manufacturing process. Cellular manufacturing protocols directly impact CAR T cell yield, phenotype and metabolism, which correlates with in vivo potency and persistence. Although metabolic fitness is a critical quality attribute, how T cell metabolic requirements vary throughout the manufacturing process remains unexplored. Here we use optical metabolic imaging (OMI), a non-invasive, label-free method to evaluate single-cell metabolism. Using OMI, we identified the impacts of media composition on CAR T cell metabolism, activation strength and kinetics, and phenotype. We demonstrate that OMI parameters can indicate cell cycle stage and optimal gene transfer conditions for both viral transduction and electroporation-based CRISPR/Cas9. In a CRISPR-edited anti-GD2 CAR T cell model, OMI measurements allow accurate prediction of an oxidative metabolic phenotype that yields higher in vivo potency against neuroblastoma. Our data support OMI as a robust, sensitive analytical tool to optimize manufacturing conditions and monitor cell metabolism for increased CAR T cell yield and metabolic fitness.
    DOI:  https://doi.org/10.1038/s41551-025-01504-7
  12. Leukemia. 2025 Sep 19.
    The endogenous T cell landscape is reshaped by CAR-T cell therapy and predicts treatment response in multiple myeloma.
    Julia Frede, Julia C Poller, Kayleen Shi, Hannah Stuart, Noori Sotudeh, Claire Havig, Klothilda Lim, Caroline R M Wiggers, Eugene Y Cho, Tushara Vijaykumar, Jianlin Liu, Johannes M Waldschmidt, Monica S Nair, Praveen Anand, Valeriya Dimitrova, Anna Montanaro, Andrew J Yee, Nikhil C Munshi, Kenneth C Anderson, Nathan Martin, Shari M Kaiser, Marc-Steffen Raab, Noopur S Raje, Birgit Knoechel, Jens G Lohr.
      While most patients initially respond to CAR-T cell treatment, responses often are not durable and subsequent lines of immunotherapy show diminishing success. In this study, we investigated the co-evolutionary dynamics between CAR-T cells and the immune microenvironment in myeloma patients undergoing anti-BCMA CAR-T cell therapy at single-cell resolution. Our findings highlight the transformative impact of CAR-T cell treatment on the endogenous T cell landscape. We identify a novel transitional CD8 + T cell population that is predictive of poor treatment outcomes. The emergence of this population coincides with the depletion of the endogenous T cell repertoire and compositional evolution of functional T cell subsets. These changes in the endogenous T cell compartment induced by CAR-T cell therapy may contribute to inadequate immune capacity and tumor control. Our findings highlight the potential of targeting TIM3/GAL9 interactions to mitigate T cell exhaustion, apoptosis and lack of persistence, offering promising avenues for optimizing T cell-based cancer immunotherapies. We provide a framework for assessing and manipulating the 'mileage' of the immune system as predictive marker and therapeutic opportunity to prevent repeated immunotherapies from becoming increasingly less successful, even when targeting distinct antigens.
    DOI:  https://doi.org/10.1038/s41375-025-02766-5
  13. Front Physiol. 2025 ;16 1655306
    Exploring the effects of exercise on T cell function and metabolism in cancer: a scoping review protocol.
    J L Low, H J Lee, B A Edgett, K Romme, S N Culos-Reed, J B Lee.
       Background: The global burden of cancer is escalating, and improved strategies for disease prevention and treatment are needed. The immune system, particularly T cells, plays a crucial role in cancer surveillance and eradication. Immunotherapy strategies that leverage the anti-cancer T cell response have significantly advanced therapeutic approaches to cancer treatment. Exercise is a lifestyle factor that naturally stimulates and strengthens the immune system. This interaction may not only be linked to the benefits of exercise in decreasing cancer risk and increasing survival but may also have the potential to be harnessed to enhance current forms of immunotherapy. Central to the exercise-immune system axis and anti-cancer control are T cells, yet little is known about how exercise might influence their function and metabolic fitness.
    Objective: We propose a scoping review with the aim to understand and summarize the current literature on the effects of exercise on T cell function and metabolism in cancer, identifying potential key mechanisms, impacts on therapeutic applications, exercise modalities, and associated outcomes.
    Methods: This scoping review will be conducted according to the methodology for scoping reviews laid out by JBI. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews (PRISMA-ScR) will be followed. Experimental studies involving i) humans OR mammals and ii) examinations of T cell function and metabolism, and iii) exercise interventions, and iv) in the context of cancer will be included.
    Results: Data search, screening and extraction will take place from June 2025-December 2025. Preliminary searches conducted while developing the initial search strategy resulted in an estimated ∼700-1000 titles and abstracts for initial screening.
    Conclusion/Implications/Dissemination: The proposed scoping review will be submitted for publication upon completion. The potential findings hold profound implications for future research in this field, providing mechanistic insights into the exercise-immune system axis that can be leveraged to enhance immune-based approaches for cancer prevention, treatment, and long-term survivorship.
    Keywords:  cancer; exercise; immune cells; immunotherapy; t cells
    DOI:  https://doi.org/10.3389/fphys.2025.1655306
  14. Proc Natl Acad Sci U S A. 2025 Sep 23. 122(38): e2510576122
    USP14-mediated metabolic competition impairs CD8+ T cell immunosurveillance in hepatocellular carcinoma.
    Yichuan Yuan, Yi Niu, Zhenkun Huang, Yunxing Shi, Zhu Lin, Dinglan Zuo, Chengrui Zhong, Kai Li, Xin-Yuan Guan, Yunfei Yuan, Binkui Li.
      Hepatocellular carcinoma (HCC) frequently develops resistance to CD8+ T cell-based immunotherapy, yet the mechanisms driving this immune evasion remain poorly understood. To identify tumor-intrinsic regulators of immunotherapy resistance and explore therapeutic strategies to restore T cell-mediated tumor control, we employed three functional genomics approaches using in vitro and in vivo CRISPR screening. Cancer USP14 was identified as the critical immune evasion driver. USP14-high HCC patients exhibited poorer anti-PD1 antibody therapy responses and reduced CD8+ T cell infiltration. Inhibition of USP14 suppressed HCC cell growth in coculture with activated CD8+ T cells and restored cocultured CD8+ T cell cytotoxicity. In vivo USP14 targeting synergized with anti-PD1 antibody therapy. Mechanistically, USP14 deubiquitinated and stabilized GLUT1 through the removal of Lys-48-linked ubiquitin chains at Lys-245, which enabled HCC cells to outcompete CD8+ T cells for glucose, generating a glucose-deprived tumor microenvironment that suppressed CD8+ T cell function. Our findings show USP14 in cancer has a proimmunoevasive role in CD8+ T cell-based tumor immunity through GLUT1-mediated glucose competition. These findings position USP14 inhibitors as promising adjuvants to enhance immunotherapy efficacy in HCC, providing actionable insights for overcoming resistance.
    Keywords:  GLUT1; USP14; glucose competition; hepatocellular carcinoma
    DOI:  https://doi.org/10.1073/pnas.2510576122
  15. Stem Cells Transl Med. 2025 Sep 11. pii: szaf041. [Epub ahead of print]14(9):
    Metabolic regulation in the senescence process of stem cells.
    YingYing Wei, Bin Zhang, Qingli Bie, Baoyu He.
       BACKGROUND: Aging is an inevitable and complex biological process characterized by progressive cellular and functional deterioration, leading to increased disease susceptibility and mortality. Stem cells, endowed with unique self-renewal and multipotent differentiation capabilities, play a pivotal role in tissue homeostasis and regenerative processes. However, the aging process triggers stem cell senescence, manifested by diminished proliferative capacity and differentiation potential, ultimately compromising tissue regeneration and contributing to the pathogenesis of various age-related disorders, including neurodegeneration, cardiovascular diseases, and metabolic syndromes.
    MAIN FINDINGS: Metabolic plasticity serves as a fundamental mechanism enabling stem cells to dynamically adapt their energy requirements during self-renewal and lineage commitment. Emerging evidence indicates that cellular metabolism extends beyond its conventional role in energy production, actively participating in the regulation of stem cell fate decisions. Notably, nutrient-sensitive metabolites constitute a sophisticated metabolism-epigenetic axis that integrates metabolic flux, signaling pathways, and epigenetic modifications to precisely orchestrate cellular behavior. This regulatory axis is indispensable for maintaining tissue homeostasis and facilitating regeneration, thereby positioning metabolic reprogramming as a promising therapeutic strategy for mitigating aging-associated decline.
    CONCLUSIONS: In conclusion, elucidating the intricate crosstalk between stem cell metabolism and the aging process unveils novel opportunities for developing innovative anti-aging interventions and enhancing tissue repair. Future investigations should focus on the precise manipulation of metabolic pathways to effectively counteract age-related functional deterioration and promote longevity.
    Keywords:  anti-aging interventions; metabolic reprogramming; metabolites; stem cell senescence; therapeutic targets
    DOI:  https://doi.org/10.1093/stcltm/szaf041
  16. Cancer Lett. 2025 Sep 11. pii: S0304-3835(25)00608-1. [Epub ahead of print]633 218038
    Lactate metabolic checkpoint in immuno-oncology: mechanisms and therapeutic implications.
    Zhe Wang, Ziyan Gu, Wendi Mo, Haijun Zhang.
      Immuno-Oncology has transformed cancer therapeutics, yet its clinical efficacy remains limited by the immunosuppressive tumor microenvironment (TME). Once considered merely a metabolic byproduct of glycolysis, lactate is now recognized as a critical regulator of immune TME through both direct metabolic effects and its derivative modification, histone lysine lactylation (Kla). Within the TME, lactate and Kla reprogram signaling pathways that impair immune function, thereby facilitating tumor immune escape. This review synthesizes emerging evidence positioning lactate metabolism and histone Kla as pivotal immunosuppressive modulators within the TME. Tumor-derived lactate, produced through the Warburg effect, acidifies the TME and disrupts immune cell function via two interconnected mechanisms: direct metabolic interference and epigenetic reprogramming via Kla. Histone Kla represents a novel post-translational modification that drives immunosuppressive signaling in immune cells, serving as a prognostic biomarker across multiple cancers. Moreover, we highlight therapeutic strategies targeting lactate metabolism, which show considerable promise in overcoming the current limitations of immunotherapy and enhancing its clinical efficacy.
    Keywords:  Immunotherapy; Lactate; Lactylation; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2025.218038
  17. ACS Pharmacol Transl Sci. 2025 Sep 12. 8(9): 2868-2886
    Harnessing Metabolism to Combat Neurodegeneration: Strategies for Reversing Age-Related Cognitive Decline.
    Smita Jain, Reetuparna Acharya, Lavkush Verma, Aparna Chauhan.
      Age-related cognitive decline, a hallmark of neurodegenerative disorders such as Alzheimer's disease, has been increasingly associated with metabolic dysregulation. Targeting metabolic pathways to enhance brain function and slow neurodegeneration presents a novel therapeutic approach. This review discusses key metabolic interventions that may reverse or delay cognitive decline. Mitochondrial dysfunction, oxidative stress, and impaired energy metabolism are central to neurodegenerative progression. Therapies aimed at boosting mitochondrial biogenesis, such as nicotinamide adenine dinucleotide (NAD+) precursors, adenosine monophosphate-activated protein kinase (AMPK) activators, and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) modulators, have shown promise in improving neuronal energy balance and reducing oxidative damage. Metabolic interventions like caloric restriction, intermittent fasting, and ketogenic diets have demonstrated neuroprotective effects by enhancing insulin sensitivity, promoting autophagy, and shifting the brain's energy reliance toward ketone bodies, which improves cognitive function. These strategies also mitigate neuroinflammation, a key driver of neuronal damage, by modulating immune responses and reducing the accumulation of toxic protein aggregates. Lipid metabolism also plays a crucial role in maintaining neuronal integrity. Enhancing lipid turnover, optimizing fatty acid profiles, and regulating cholesterol homeostasis may improve synaptic plasticity and reduce neuroinflammation, offering additional therapeutic avenues. By integrating current insights into metabolic regulation, this review underscores the potential of metabolic therapies to reverse or mitigate the cognitive decline associated with aging. Advancing our understanding of the intricate relationship between metabolism and neurodegeneration may pave the way for novel treatments targeting age-related cognitive impairment.
    Keywords:  caloric restriction; insulin signaling; lipid metabolism; mitochondrial dysfunction; neurodegeneration
    DOI:  https://doi.org/10.1021/acsptsci.5c00077
  18. Trends Cancer. 2025 Sep 12. pii: S2405-8033(25)00205-5. [Epub ahead of print]
    The emerging roles of the urea cycle in tumor microenvironment and therapies.
    Jiawen Zhou, Xuan Sun, Peng Jiang.
      The urea cycle (UC) is a vital metabolic pathway that is responsible for the disposal of nitrogen and the production of metabolites necessary for biosynthesis. UC dysregulation is common in various cancers and impacts on cellular metabolism and the tumor microenvironment (TME). In this review we explore alterations in the expression of UC genes and metabolites in tumors, focusing on their roles in tumor progression, the TME, and cancer therapies. We discuss the effects of the UC on immune responses involving T cells and immunosuppressive cells, as well as on stromal cells and angiogenesis. We highlight the impact of arginine and polyamine metabolism in the TME. Although therapeutic strategies targeting the UC show promise, including arginine deprivation therapy (ADT), they face challenges such as drug resistance and toxicity. It will be essential to elucidate the specific functions of UC enzymes in tumorigenesis to devise more effective, personalized tumor therapies. Future studies should focus on combination therapies and personalized medicine to improve efficacy and patient prognosis.
    Keywords:  arginine deprivation therapy; metabolic reprogramming and sensing; tumor cell metabolism; tumor microenvironment; urea cycle (UC)
    DOI:  https://doi.org/10.1016/j.trecan.2025.08.007
  19. Mol Ther Methods Clin Dev. 2025 Sep 11. 33(3): 101570
    Effects of CRISPR-Cas9-mediated FOXP3 knockout on CAR T cell potency.
    Lena Peter, Martí Farrera-Sal, Ferhat Ali Yaman, Nils Henrik Dempewolf, Samira Picht, Sarah Schulenberg, Jonas Kath, Frederik Hamm, Frederik Heinrich, Dimitrios L Wagner, Mir-Farzin Mashreghi, Annette Künkele, Petra Reinke, Julia K Polánsky, Michael Schmueck-Henneresse.
      Persistent antigen stimulation and inflammatory environments drive exhaustion, senescence, and activation-induced cell death, impairing both endogenous and therapeutic T cells. Understanding the mechanisms underlying T cell dysfunction is critical for improving immunotherapies. While the transcription factor forkhead box protein P3 (FOXP3) is primarily known for its role in regulatory T cell development and maintenance, recent studies suggest it may also influence effector T cell function. However, its impact on therapeutic T cells, including CAR T cells, remains poorly defined. Here, we used non-viral CRISPR-Cas9 editing to knockout FOXP3 in CD19-directed CAR T cell products (TCPs) generated via lentiviral transduction. FOXP3 expression was upregulated at both the protein and RNA level following CAR stimulation. Compared to unmodified CAR TCPs, FOXP3-KO CAR TCPs showed comparable exhaustion profiles but enhanced cytokine production and prolonged cytotoxic function across repeated antigen challenges. These findings identify FOXP3 as a context-dependent modulator of CAR T cell function and suggest that its disruption may enhance therapeutic potency without exacerbating exhaustion. FOXP3 targeting may represent a complementary strategy to improve the functional resilience of CAR T cell therapies in cancer or autoimmune disease.
    Keywords:  CAR T cell potency; CAR T cells; CRISPR-Cas9; FOXP3; T cell exhaustion; cytotoxicity; effector T cells; gene editing; immunomodulation; immunotherapy
    DOI:  https://doi.org/10.1016/j.omtm.2025.101570
  20. Biomed Pharmacother. 2025 Sep 17. pii: S0753-3322(25)00754-1. [Epub ahead of print]192 118560
    Microbiota-derived butyrate potentiates MSLN CAR-T cell therapy by metabolic reprogramming and extracellular matrix remodeling.
    Jiannan Chen, Wenying Li, Lindong Yang, Jiayi Li, Shuai Wang, Zhengliang Chen, Shichu Xu, Mengru Wen, Junqing Liang, Zhigang Hu, Feiyan Pan, Lingfeng He, Lili Gu, Zhiqiang Wang, Haoyan Chen, Zhigang Guo.
      Despite the success of chimeric antigen receptor (CAR)-T cell therapy in hematologic malignancies, its efficacy in solid tumors remains limited due to T cell dysfunction and immunosuppressive microenvironments. Emerging evidence suggests that gut microbiota-derived metabolites, particularly short-chain fatty acids (SCFAs), may enhance T cell function, but their role in CAR-T therapy is unexplored. Here, in a small patient cohort (n = 4), preliminary metagenomic and metabolomics data suggested an association between higher butyrate levels and improved CAR-T responses, motivating our investigation of sodium butyrate (NaB), a microbiota-derived short-chain fatty acid, as a potential enhancer of CAR-T cell function through integrated metabolic and transcriptional reprogramming. Functional screening showed that NaB treatment augmented CAR-T cell antitumor activity while promoting a memory-like phenotype and reducing exhaustion markers. Mechanistically, NaB amplified antigen-driven phosphorylation of signaling effectors (p-ERK1/2, p-ZAP-70, p-AKT), inducing dual activation of glycolytic and oxidative phosphorylation pathways, coupled with upregulation of extracellular matrix (ECM)-remodeling genes (MMPs, Collagens), thereby improving tumor homing capacity. These preliminary findings suggest NaB as a potential link between microbial metabolism and CAR-T cell efficacy, offering a promising yet exploratory strategy to optimize adoptive immunotherapy through signaling-metabolic-ECM crosstalk, pending validation in larger cohorts.
    Keywords:  CAR-T cell therapy; ECM remodeling; Gut Microbiota; Metabolic reprogramming; SCFA; Signaling pathways
    DOI:  https://doi.org/10.1016/j.biopha.2025.118560
  21. Trends Cancer. 2025 Sep 16. pii: S2405-8033(25)00204-3. [Epub ahead of print]
    Optimizing mitochondria function in immune cells: implications for cancer immunotherapy.
    Huiyu Li, Wenyi Jin, Junhong Liu, Yundong Zhou, Xiaoli Shan, Yubiao Zhang, Yongliang Kou, Chunyan Deng, Cheng Jin, Junjie Kuang, Yui-Leung Lau, João Conde, Baozhen Huang, Queran Lin.
      The tumor microenvironment (TME) imposes profound metabolic and functional constraints on immune cells, with mitochondrial dysfunction emerging as a pivotal driver of immunosuppression. While mitochondrial metabolism is well recognized for its role in energy production and cellular homeostasis, its dynamic regulation of immune cell activation, differentiation, and exhaustion within the TME remains underexplored. In this review we summarize insights into how TME stressors such as hypoxia, nutrient competition, and metabolic byproducts subvert mitochondrial dynamics, redox balance, and mitochondrial DNA (mtDNA) signaling in T cells, natural killer (NK) cells, and macrophages, thereby directly impairing their antitumor efficacy. We emphasize that the restoration of mitochondrial fitness in immune cells, achieved by targeting metabolites in the TME and mitochondrial quality control, represents a pivotal axis for adoptive cell therapies (ACTs) and TME reprogramming.
    Keywords:  ROS; chimeric antigen receptor (CAR); metabolism; mitochondria; tumor immunotherapy
    DOI:  https://doi.org/10.1016/j.trecan.2025.08.006
  22. bioRxiv. 2025 Sep 01. pii: 2025.08.30.673239. [Epub ahead of print]
    Reprogramming Factors Activate a Non-Canonical Oxidative Resilience Pathway That Can Rejuvenate RPEs and Restore Vision.
    Yuancheng Ryan Lu, James C Cameron, Yan Hu, Han Shen, Shintaro Shirahama, Alexander Tyshkovskiy, Zhaoyi Chen, Jiahe Ai, Daniel Y Zhu, Margarete M Karg, Lindsey A Chew, George W Bell, Siddhartha G Jena, Yue He, Philip Seifert, Daisy Y Shu, Mohamed A Ei-Brolosy, Qiannuo Lou, Bohan Zhang, Anna M Puszynska, Xiaojie Qiu, Xiao Tian, Meredith Gregory-Ksander, Vadim N Gladyshev, David A Sinclair, Magali Saint-Geniez, Jason D Buenrostro, Catherine Bowes Rickman, Bruce R Ksander, Jonathan S Weissman.
      Oct4, Sox2, and Klf4 (OSK) Yamanaka factors induce pluripotency and reverse age-related epigenetic changes, yet the mechanisms by which they promote rejuvenation remain poorly explored. Oxidative stress contributes to CNS aging and retinal pigmented epithelium (RPE) degeneration in age-related macular degeneration. We find that OSK expression in RPE restores retinal structure and visual function in aged mice and promotes oxidative resilience through a non-canonical, Tet2-independent pathway. Integrative functional genomics identifies GSTA4, a detoxifying enzyme that clears the lipid peroxidation byproduct 4-HNE, as a necessary and sufficient OSK effector. Dynamic GSTA4 regulation by OSK recapitulates a stem cell derived stress resilience program. GSTA4 overexpression alone enhances mitochondrial resilience, rejuvenates the aged RPE transcriptome, and reverses visual decline. GSTA4 is consistently upregulated across diverse lifespan-extending interventions suggesting a broader pro-longevity role. These findings uncover a previously unrecognized protective axis driven by Yamanaka factors that circumvents reprogramming, providing therapeutic insights for age-related diseases.
    HIGHLIGHTS: OSK-GSTA4 provides a dynamic, Tet2-independent stress-resilience axis.Functional genomics pinpoints GSTA4 as a direct downstream effector activated by OSK.RPE aging involves progressive accumulation of 4-HNE that can be detoxified by GSTA4.Enhancing GSTA4 rejuvenates RPE cells, restores vision and is associated with lifespan-extending interventions.
    DOI:  https://doi.org/10.1101/2025.08.30.673239
  23. Cancer Discov. 2025 Sep 19.
    Activation of T cell-intrinsic p53 by acetylation elicits antitumor immunity to boost cancer immunotherapy.
    Xiaojun Yan, Wenbin Xu, Han Yao, Zhen Wu, Jingyuan Ning, Shidong Zhao, Yajing Liu, Meng Zhang, Dongkui Xu, Zhanlong Shen, Wei Gu, Donglai Wang.
      Although p53 plays a central role in tumor suppression, how it is regulated in T cells to exert antitumor effects remains unclear. Here, we show that activation of T cell-intrinsic p53 via carboxyl-terminal domain (CTD) acetylation during immunotherapy activates the IFN-γ pathway, promotes CD8+ T cell infiltration, and elicits CD8+ T cell-dependent antitumor immunity. Using T cell-specific knockin mouse models, we demonstrate that loss of CTD acetylation in T cells abrogates CD8+ T cell-dependent antitumor immunity whereas expression of CTD acetylation-mimicking p53 in T cells enhances this immune response. Moreover, we identify IFNG as a direct target of T cell-intrinsic p53 and uncover a positive feedback loop between p53 and the IFN-γ pathway for enhancing T cell-dependent antitumor immunity. Our study reveals that CTD acetylation-mediated activation of T cell-intrinsic p53 promotes antitumor immunity in response to immunotherapy, highlighting a non-tumor cell-autonomous mechanism of p53 action by regulating adoptive immune responses.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-0649
  24. bioRxiv. 2025 Sep 04. pii: 2025.08.29.673172. [Epub ahead of print]
    A thymus-independent artificial organoid system supports complete thymopoiesis from Rhesus macaque-derived hematopoietic stem and progenitor cells.
    Callie Wilde, Saleem Anwar, Yu-Tim Yau, Sunil Badve, Yesim Gokmen Polar, John D Roback, Rama Rao Amara, R Paul Johnson, Sheikh Abdul Rahman.
      Thymic output has been extensively studied. While advanced ex-vivo T cell generative approaches exist for mouse and human models, such advancements for nonhuman primate model are lacking. We report the establishment of a rhesus macaque-specific artificial thymic organoid (Rh-ATO) system enabling robust ex vivo T cell generation from CD34⁺ hematopoietic stem and progenitor cells (HSPCs). A continuum of distinct thymopoietic stages were recorded - robust T cell specification of HSPCs resembling thymus seeding progenitors, emergence of CD4+CD3-immature single positive, CD4+CD8+ double positive thymocytes, and finally, generation of CD4⁺ and CD8⁺ single-positive T cell subsets expressing CD38, consistent with recent thymic emigrant phenotype. These events closely mirrored Bonafide thymopoietic stages observed in the thymus. T cells expressed TCRs and exhibited polyfunctional cytokine expression. Thus, we report first demonstration of an off the shelf NHP-specific 3D system recapitulating thymopoiesis, providing a translational platform for modeling T cell development, therapeutic strategies, and immunopathogenesis.
    DOI:  https://doi.org/10.1101/2025.08.29.673172
  25. Nat Genet. 2025 Sep 15.
    Advancing biological understanding of cellular senescence with computational multiomics.
    SenNet Consortium
      Cellular senescence is a complex biological process that plays a pathophysiological role in aging and age-related diseases. The biological understanding of senescence at the cellular and tissue levels remains incomplete due to the lack of specific biomarkers as well as the relative rarity of senescent cells, their phenotypic heterogeneity and dynamic features. This Review provides a comprehensive overview of multiomic approaches for the characterization and biological understanding of cellular senescence. The technical capability and challenges of each approach are discussed, and practical guidelines are provided for selecting tools for identifying, characterizing and spatially mapping senescent cells. The importance of computational analyses in multiomics research, including senescent cell identification, signature detection and interactions of senescent cells with microenvironments, is highlighted. Moreover, tissue-specific case studies and experimental design considerations for individual organs are presented. Finally, future directions and the potential impact of multiomic approaches on the biological understanding of cellular senescence are discussed.
    DOI:  https://doi.org/10.1038/s41588-025-02314-y
  26. Aging Adv. 2025 Sep;2(3): 108-111
    Mitoepigenetic Targeting of Age-Related Dysfunction: Mechanisms, Therapeutic Avenues, and Transgenerational Implications.
    Kit Neikirk, Suraj Thapliyal, Sepiso K Masenga, Ashton Oliver, Margaret Mungai, Han Le, Heather K Beasley, Andrea G Marshall, Anthonya T Cooper, Taneisha Gillyard Cheairs, Benjamin I Rodriguez, Edgar Garza-Lopez, Prasanna Katti, Antentor Hinton.
      Mitochondrial epigenetics, a burgeoning field bridging mitochondrial biology and epigenetic regulation, has emerged as a critical determinant of aging and age-related diseases. While nuclear epigenetics is well-characterized, the mechanisms governing mitochondrial DNA (mtDNA) regulation, including nucleoid dynamics, non-coding RNAs (ncRNAs), and metabolite-driven modifications, remain underexplored. This review synthesizes evidence that mitochondrial epigenetics influences cardiovascular pathogenesis through altered DNA methylation and histone acetylation patterns, which dysregulate oxidative phosphorylation and nucleoid stability. In neurodegenerative diseases, endoplasmic reticulum-mitochondrial contact points, disrupted by aging, impair calcium homeostasis and promote neuronal apoptosis, while oxidative stress exacerbates mtDNA instability through inefficient repair mechanisms. Cancer cells exploit mitochondrial metabolic reprogramming, where shifts in acetyl-CoA and α-ketoglutarate levels modulate epigenetic enzymes, fostering drug resistance. Potential therapeutic targets include pharmacological modulation of Mitochondrial transcription factor A acetylation/phosphorylation to enhance mtDNA transcription and dietary interventions to boost NAD+ levels, thereby improving mitochondrial function. Transgenerational studies reveal matrilineal inheritance of mtDNA methylation patterns and stress-induced epigenetic memory, though technical limitations in detecting mtDNA methylation persist. Clinically, mitochondrial epigenetic biomarkers like mtDNA hydroxymethylation and lncRNA expression (e.g., Mitoregulin) show promise for early diagnosis and treatment monitoring. Despite advances, challenges include standardizing methods for mtDNA methylation analysis and translating preclinical findings into therapies. This perspective review underscores the need for integrative approaches combining single-cell sequencing and CRISPR-based technologies to dissect mitochondrial-nuclear crosstalk, ultimately paving the way for precision medicine strategies targeting mitoepigenetic pathways to mitigate age-related decline.
    Keywords:  aging; epigenetics; methylation; mitochondria; mitochondrial nucleoid; mtDNA
    DOI:  https://doi.org/10.4103/agingadv.agingadv-d-25-00006
  27. mBio. 2025 Sep 15. e0353723
    Step-by-step: the CD8 T cell journey in leishmaniasis.
    Erin A Fowler, Fernanda O Novais.
      Leishmaniasis is a group of vector-borne diseases caused by protozoan parasites of the genus Leishmania that affect millions of people across nearly 100 countries. Clinical presentations range from self-resolving cutaneous ulcers to life-threatening visceral disease, depending on the infecting species and host immune response. While CD4 T cells have long been recognized as central to parasite control, CD8 T cells also play an important role in disease. In this mini-review, we explore the many steps involved in CD8 T cell responses in leishmaniasis, with a focus on antigen recognition, recruitment, effector function, memory development, and dysfunction. Drawing on both murine models and human studies, we highlight the duality of CD8 T cells, which can contribute to protection but also drive immune-mediated tissue damage. Recent advances in transcriptomics, in vivo modeling, and immunophenotyping have begun to clarify the conditions under which CD8 T cells support vs hinder host defense. Despite this progress, critical questions remain, and continued investigation into the heterogeneity and regulation of CD8 T cells in leishmaniasis promises not only to deepen our understanding of host-pathogen interactions but also to guide the development of targeted immunotherapies and vaccines.
    Keywords:  CD8 T cells; Leishmania; parasites
    DOI:  https://doi.org/10.1128/mbio.03537-23
  28. bioRxiv. 2025 Sep 11. pii: 2025.09.10.675369. [Epub ahead of print]
    Tumor Genotype Dictates Mitochondrial and Immune Vulnerabilities in Liver Cancer.
    Gokhan Unlu, Alon Millet, Khando Wangdu, Romain Donné, Ranya Erdal, Nicole L DelGaudio, Beste Uygur, Vyom Shah, Kevin Cho, Antonia Fecke, Feyza Cansiz, Zeynep Cagla Tarcan, Michael Isay-Del Viscio, Ece Kilic, Isabel Kurth, Henrik Molina, Albert Sickmann, Olca Basturk, Gary Patti, Semir Beyaz, Karl W Smith, Amaia Lujambio, Alpaslan Tasdogan, Sohail F Tavazoie, Kıvanç Birsoy.
      Although oncogenic alterations influence tumor metabolism, how they impose distinct metabolic programs within a shared tissue context remains poorly defined. Here, we developed a rapid mitochondrial profiling platform to compare metabolites and proteins in genetic models of primary liver cancer (PLC). Analyses of six genetically distinct PLCs revealed that mitochondrial energy metabolism is largely dictated by oncogene identity. Kras -driven tumors required creatine metabolism to buffer energy demands during early tumorigenesis, whereas c-MYC -driven tumors relied on oxidative phosphorylation. Among c-MYC -driven PLCs, Pten -deficient tumors accumulated mitochondrial phosphoethanolamine, a precursor for phosphatidylethanolamine (PE) synthesis. Inhibition of PE synthesis selectively impaired the growth of Pten -deficient tumors and extended survival, in part through enhanced infiltration of CD8⁺ T cells and sensitization to TNFα-mediated cytotoxicity. Mechanistically, loss of PE elevated surface TNF receptor 2 (TNFR2), promoting TNFα signaling and pro-inflammatory response. These findings uncover genotype-specific mitochondrial metabolic liabilities and establish PE synthesis as a tumor-intrinsic mechanism of immune evasion in PLC.
    DOI:  https://doi.org/10.1101/2025.09.10.675369
  29. Trends Cancer. 2025 Sep 18. pii: S2405-8033(25)00225-0. [Epub ahead of print]
    CAR T cell persistence in cancer.
    Katherine P Mueller, Jeremy M Grenier, Evan W Weber.
      Chimeric antigen receptor T cell (CAR T) therapies are 'living drugs' in which T cells are genetically engineered to recognize and kill cancer cells. A major barrier to progress for CAR T targeting liquid and solid tumors is the poor persistence of these cells in vivo, which limits therapeutic efficacy. In this review, we summarize the field's current understanding of CAR T persistence, including clinical observations, patient correlatives and multiomics approaches, and emerging cell engineering and manufacturing strategies. We also propose a conceptual framework for CAR T persistence to guide interpretation of clinical data and the design of more potent and efficacious CAR T therapeutics.
    Keywords:  CAR T; T cell exhaustion; cancer; immunotherapy; persistence
    DOI:  https://doi.org/10.1016/j.trecan.2025.08.014
  30. Front Genet. 2025 ;16 1686852
    Editorial: Mitochondria in metabolic reprogramming and immune activation: the key gene and therapeutic target.
    Yongzheng Guo.
      
    Keywords:  immunometabolic crosstalk; inflammation; metabolic reprogramming; mitochondria; therapeutic targeting
    DOI:  https://doi.org/10.3389/fgene.2025.1686852
  31. JCI Insight. 2025 Sep 16. pii: e192286. [Epub ahead of print]
    Intrinsic T cell glutaminolysis promotes autoimmunity in lupus-prone mice.
    Seung-Chul Choi, Yong Ge, Milind V Joshi, Damian Jimenez, Abigail Castellanos Garcia, Cassandra LaPlante, Lauren T Padilla, Chaoyu Ma, Nu Zhang, Jeffrey C Rathmell, Mansour Mohamadzadeh, Laurence Morel.
      Glutaminolysis is enhanced in T cells of lupus patients and in follicular helper T (Tfh) cells, a critical subset of CD4+ T cells that provide help to autoreactive B cells, in lupus mice. Glutaminolysis inhibitors reduced lupus activity in association with a decreased frequency of Th17 cells in mice. Here, we thought to determine the role of glutaminolysis in murine Tfh cells. The pharmacological inhibition of glutaminolysis with DON reduced the expression of the critical costimulatory molecule ICOS on lupus Tfh cells, in association with a reduction of autoantibody production and B cell differentiation markers. Accordingly, profound transcriptomic and metabolic changes, including a reduction of glycolysis, were induced by DON in lupus Tfh cells, whereas healthy Tfh cells showed minor changes. The T cell-specific genetic inhibition of glutaminolysis largely phenocopied the effects of DON on Tfh cells and B cells in an autoimmune genetic background with minor changes in Tfh and B cells in healthy controls. Furthermore, we showed that T cell-specific glutaminolysis inhibition impaired T-dependent humoral responses in autoimmune mice as well as their Tfh response to a viral infection. Overall, these results suggest that lupus Tfh cells have a greater intrinsic requirement of glutaminolysis for their helper functions.
    Keywords:  Adaptive immunity; Amino acid metabolism; Autoimmunity; Immunology; T cells
    DOI:  https://doi.org/10.1172/jci.insight.192286
  32. Blood. 2025 Sep 19. pii: blood.2024027496. [Epub ahead of print]
    Reprogramming glutamine metabolism enhances BCMA-CART cell fitness and therapeutic efficacy in multiple myeloma.
    Flor Navarro, Teresa Lozano, Andrea Fuentes-García, Inés Sánchez-Moreno, Marta Larrayoz, Pedro Justicia, Beatriz Perucha, Maialen Martinez-Tabar, Rebeca Martinez-Turrillas, Noelia Casares, Celia Martín-Otal, Marta Gorraiz, Erin W Meermeier, Marta Chesi, Douglas Lake, Paul Leif Bergsagel, Eva Santamaría, Maria Erendira Calleja-Cervantes, Patxi San Martín-Úriz, Lorea Jordana-Urriza, Xabier Agirre, Sandra Hervas-Stubbs, Juan Roberto Rodriguez-Madoz, Jose A Martínez-Climent, Felipe Prosper, Juan J Lasarte.
      Glutamine-dependence of cancer cells reduces local glutamine availability, which hinders anti-tumor T-cell functionality and facilitates immune evasion. We thus speculated that glutamine deprivation might be limiting efficacy of CAR T-cell therapies in cancer patients. We have seen that antigen-specific T cells are unable to proliferate or produce IFN-γ in response to antigen stimulation when glutamine concentration is limited. Using multiple myeloma (MM) as a glutamine-dependent disease model, we found that murine CAR-T cells selectively targeting BCMA in MM cells were sensitive to glutamine deprivation. However, CAR-T cells engineered to increase glutamine uptake by expression of the glutamine transporter Asct2 exhibited enhanced proliferation and responsiveness to antigen stimulation, increased production of IFN-γ, and heightened cytotoxic activity, even under conditions of low glutamine concentration. Mechanistically, Asct2 overexpression reprogrammed CART cell metabolic fitness of CART cells by upregulating the mTORC1 gene signature, modifying the Solute Carrier transporter (SLC) repertoire, and improving both basal oxygen consumption rate and glycolytic function thereby enhancing CART cell persistence in vivo. Accordingly, expression of Asct2 increased the efficacy of BCMA-CART cells in syngeneic and genetically-engineered mouse models of MM, which prolonged mouse survival. In patients, reduced expression of Asct2 by MM cells predicted poor outcome to combined immunotherapy and BCMA-CAR T-cell therapy. Our results indicate that reprogramming glutamine metabolism may enhance anti-tumor CAR T-cell functionality in MM. This approach may also be effective for other cancers that depend on glutamine as a key energy source and metabolic hallmark.
    DOI:  https://doi.org/10.1182/blood.2024027496
  33. bioRxiv. 2025 Sep 10. pii: 2025.09.05.674535. [Epub ahead of print]
    TNFR2 is Expressed by a Discrete Subset of Epidermal γδ T Cells with an IL-17 Gene Signature during Psoriasis.
    Jasmine Ahmed, Carolyn Matthews, Patricia Tulloch, William Lawler, Albert Mendoza, Mikaela Rhoiney, Julie M Jameson.
      Psoriasis is a chronic skin disease that results in scaly patches and affects 2-3% of people worldwide. Therapeutic treatment targets the TNF-α/IL-17 axis to disrupt keratinocyte hyperproliferation and inflammation. While more is known about the role of dermal αß and γδ T cells in IL-17 production, less is understood about the role of resident epidermal T cells. Here, we examine how TNF-α modulates epidermal γδ T cell activation and function. We show that a subset of activated epidermal γδ T cells expresses TNFR2 with or without TNFR1. Stimulation with TNF-α induces epidermal γδ T cells to produce IL-17 family cytokines and chemokines. Epidermal γδ T cells do not require TNFR1 or 2 for development or homing to the skin. Instead, TNFR2 plays roles in epidermal γδ T cell function skewing them toward a Tγδ17 phenotype during psoriasis. Investigation of the mechanisms by which TNF-α associated inflammation impacts epidermal γδ T cell function may help identify new cellular targets for immunotherapy or mark them as early regulators of skin inflammation.
    DOI:  https://doi.org/10.1101/2025.09.05.674535
  34. Cell Rep. 2025 Sep 17. pii: S2211-1247(25)01067-8. [Epub ahead of print]44(10): 116296
    Mitochondrial-activity-driven hematopoietic stem cell fate and lineage choice is first established in the aorta-gonad-mesonephros.
    Aishwarya Prakash, Maneesha S Inamdar.
      Mitochondrial metabolism determines bone marrow hematopoietic stem cell (HSC) heterogeneity and influences their repopulation potential, though its embryonic origins remain unclear. We show that during the endothelial-to-hematopoietic transition in the mouse embryo, dynamic changes in mitochondrial activity drive the production of hematopoietic stem and progenitor cells (HSPCs) with differing potencies. Lowering mitochondrial activity in the aorta-gonad-mesonephros (AGM) by pharmacological or genetic means activates Wnt signaling to promote HSPC expansion. Further, mitochondrial membrane potential (MMP) gives rise to functional heterogeneity in HSPCs. In-vitro and in-vivo functional assays and single-cell transcriptomics showed that MMPlow HSPCs in the AGM are myeloid biased, with enhanced differentiation potential, whereas MMPhigh HSPCs are lymphoid biased, with diminished differentiation potential. Mechanistically, low mitochondrial activity in HSPCs upregulates phosphoinositide 3-kinase signaling to promote differentiation. These insights into the initiation of metabolic heterogeneity could be leveraged to isolate the distinct HSPC subsets and to efficiently generate the desired lineages.
    Keywords:  CP: Developmental biology; PI3K signaling; Wnt signaling; cell fate; endothelial to hematopoietic transition; hematopoiesis; hematopoietic stem and progenitor cell; lymphoid; metabolism; mitochondria; myeloid
    DOI:  https://doi.org/10.1016/j.celrep.2025.116296
  35. PLoS One. 2025 ;20(9): e0332406
    Exploratory trajectory inference reveals convergent lineages for CD8 T cells in chronic LCMV infection.
    Jan T Schleicher, Revant Gupta, Dario Cerletti, Ioana Sandu, Annette Oxenius, Manfred Claassen.
      Trajectory inference refers to the task of reconstructing state sequences of dynamic processes from single-cell RNA sequencing (scRNAseq) data. This task frequently results in ambiguous results due to the noisiness of the data. While this issue has been alleviated by the incorporation of directional information from RNA velocity analyses, it remains difficult to resolve complex differentiation topologies, such as convergent trajectories. We introduce exploratory trajectory inference to address this challenge. This approach considers unsupervised clustering analysis of trajectory ensembles derived from simulation-based trajectory inference to deduce differentiation lineages in a data-driven fashion. We assess this approach to resolve the convergent differentiation trajectories in CD8 T-cell differentiation in chronic infections. We utilize an original scRNAseq time-series dataset of CD8 T cells collected during the time course of a chronic LCMV infection. Simulation-based trajectory inference identified a branch region early during chronic infection where cells separate into an exhausted and a memory-like lineage. Exploratory trajectory inference further allowed us to identify a convergent differentiation trajectory traversing memory-like states and ending in the exhausted population. Adoptive transfer experiments showed CD8 T cells with predicted memory-like fate differentiating into both memory-like and exhaustion states, confirming the convergent differentiation topology. We expect exploratory trajectory inference to be applicable in other scRNAseq-based studies aiming at comprehensive characterization of differentiation trajectories with bifurcating and convergent topologies.
    DOI:  https://doi.org/10.1371/journal.pone.0332406
  36. bioRxiv. 2025 Sep 10. pii: 2025.09.08.674524. [Epub ahead of print]
    The gut microbiota directs vitamin A flux to regulate intestinal T cell development.
    Tarun Srinivasan, Chaitanya Dende, Kelly A Ruhn, Stefanie L Moye, Ann Johnson, Cassie L Behrendt, Brian Hassell, Gonçalo Vale, Jiwoong Kim, Jake N Lichterman, Chaoying Liang, Carlos Arana, Prithvi Raj, Xiaowei Zhan, Jeffrey G McDonald, Andrew Y Koh, Lora V Hooper.
      The intestinal microbiota shapes adaptive immunity, but the mechanisms remain incompletely defined. Here, we show that the microbiota initiates the movement of retinoids-dietary vitamin A derivatives including retinol and retinoic acid-through a sequential pathway from epithelial cells to myeloid cells and ultimately to T cells in the mesenteric lymph nodes (mLNs). This cellular axis is traversed over three days. Microbe-associated molecular patterns (MAMPs) initiate retinoid flux by inducing expression of serum amyloid A (SAA) proteins. These epithelial retinol-binding proteins are necessary and sufficient for epithelial-to-myeloid cell retinoid transfer and for myeloid cell migration to the mLNs. In the mLNs, microbial antigen drives retinoid transfer from myeloid cells to developing T cells, culminating in T cell retinoid uptake and transcriptional programming. This pathway is activated during postnatal development, when gut adaptive immunity is first established. These findings reveal that the microbiota programs intestinal adaptive immunity by regulating immune cell access to a nutrient-derived developmental signal.
    Highlights: The gut microbiota enables vitamin A flux to developing intestinal CD4⁺ T cells.Microbiota-induced SAA initiates vitamin A flux along a gut myeloid-T cell axis.Microbial molecular patterns and antigen drive distinct steps of vitamin A flux.Microbiota-driven vitamin A flux programs intestinal T cell homing and maturation.
    DOI:  https://doi.org/10.1101/2025.09.08.674524
  37. Cell Rep. 2025 Sep 16. pii: S2211-1247(25)01073-3. [Epub ahead of print]44(10): 116302
    T cell-intrinsic cGAS-CTCF regulation maintains regulatory T cell development and function.
    Hongpeng Li, Yuchen Zhang, Shangze Gao, Hang Yin.
      While cGAS is known as a cytosolic DNA sensor in innate immunity, its function in T cells and adaptive immunity remains uncharacterized. This study investigates the role of cGAS in regulatory T (Treg) cells. At steady state, cGAS is located in the nucleus of Treg cells, while stimulation of naive CD4+ T cell induces its transcription and translocation into the nucleus. Using T cell and Treg cell-specific cGAS knockout mice, we demonstrate that nuclear cGAS promotes Treg cell development and function independently of its downstream adaptor STING. cGAS primes thymocytes for Treg cell differentiation during positive selection and stabilizes FOXP3. Mechanistically, nuclear cGAS recruits chromatin organizer CTCF to Tnfrsf9 (4-1BB) and Tnfrsf4 (OX40) loci via chromatin interaction to sustain their expression and TCR signaling. Treg cell-specific cGAS deletion impairs tumor growth in mice. This work reveals a STING-independent role for nuclear cGAS in adaptive immunity, establishing a cGAS-CTCF axis controlling Treg cell-mediated immune tolerance.
    Keywords:  CP: Immunology; CTCF; T(reg); TNFRSF; cGAS; chromatin interaction
    DOI:  https://doi.org/10.1016/j.celrep.2025.116302
  38. bioRxiv. 2025 Sep 11. pii: 2025.09.06.674490. [Epub ahead of print]
    Dual checkpoint blockade of glioblastoma with Anti-PD-1 and Anti-LAG-3 promotes expansion of tumor-reactive T cell clones along a unique pathway of differentiation.
    Mingshuang Wang, Yuntian Fu, Sadhana Bom, Yi Ning, Divij Matthews, Ming Zhang, Calixto-Hope Lucas, John Choi, Zhen Zeng, Tianbei Zhang, Hongkai Ji, Vasan Yegnasubramanian, Jon Weingart, Chetan Bettegowda, Kellie N Smith, Michael Lim, Drew Pardoll, Nancy R Zhang, Christina Jackson.
      IDH-wildtype grade IV glioblastoma is the most aggressive adult primary brain tumor and remains refractory to anti-PD-1 monotherapy despite evidence of limited tumor-specific T cell induction. To determine the impact of immune checkpoint inhibitors (ICIs) on glioblastoma T cell transcriptional landscape and repertoire, we conducted paired single-cell RNA sequencing (scRNA-seq) and T cell receptor sequencing (TCR-seq) of tumor-infiltrating lymphocytes (TILs) from patients with untreated, newly diagnosed glioblastoma and from recurrent glioblastoma treated with dual checkpoint blockade targeting PD-1 and LAG-3. Using a validated transcriptional signature, we found that predicted tumor-reactive T cells (TRC) in untreated glioblastomas reside almost exclusively in a clonally expanded GZMK hi population with developmental plasticity, affording them the potential to differentiate into both tissue-resident and terminal effector T cells. Dual ICI therapy induced substantial clonal remodeling, characterized by the recruitment of new TRC from the periphery into the tumor microenvironment (TME) and differentiation into transitional effectors and ultimately terminal effectors along a gradient characterized by simultaneous acquisition of cytotoxic and exhaustion genes, regulated by specific transcriptional, metabolic, and epigenetic programs. Longitudinal clonal tracking in peripheral blood confirmed that with ICI treatment, most TRC expand transiently in circulation prior to tumor infiltration, with peripherally derived clones becoming the major contributor to the GZMK hi TRC that further expand in the tumor. Our study provides the first comprehensive map of T cell clonal dynamics and differentiation in glioblastoma following dual ICIs and highlights a potential mechanism of immune activation and peripheral recruitment of TRC in glioblastoma not previously described. Our results suggest that therapeutic strategies to sustain these GZMK hi early effector and transitional effector T cells may further enhance ICI therapeutic efficacy in glioblastoma.
    DOI:  https://doi.org/10.1101/2025.09.06.674490
  39. medRxiv. 2025 Aug 08. pii: 2025.08.05.25333071. [Epub ahead of print]
    Intrathecally expanded GZMK+/GZMH+ CD8 T cells targeting EBV antigens may reduce severity of Multiple Sclerosis.
    Shinji Ashida, Peter Kosa, Francisco Otaizo-Carrasquero, Dan Sturdevant, Amirhossein Shamsaddini, Yongmei Zhao, Jyoti Shetty, Craig Martens, Jeffrey I Cohen, Bibiana Bielekova.
      Combining cerebrospinal fluid B cell receptor and T cell receptor repertoire analysis with transcriptional/ flow cytometry cellular profiles in hundreds of deeply-phenotyped people with Multiple Sclerosis (pwMS) and controls, we identified intrathecal expansion of anti-viral, cytotoxic, granzymes H/K (GZMH+/GZMK+) double positive (DP) CD8+ T cells that recognize EBV epitopes in pwMS. DP CD8+ T cells are activated and expanded by, and kill autologous, EBV-infected CSF B cell lines in-vitro. Correlations of surrogate transcriptional profiles with clinical and imaging outcomes infer a beneficial role for EBV-targeting DP CD8+ T cells, as untreated pwMS with proportionally higher DP CD8+ T cells to intrathecal B cells accumulate neurological disability slower. MS therapies also increase ratios of beneficial CD8+ T cell responses to intrathecal B cells, consistent with their ability to inhibit disability progression. This study provides indirect evidence that intrathecal EBV infection participates in disability accumulation in pwMS.
    DOI:  https://doi.org/10.1101/2025.08.05.25333071
  40. J Cancer. 2025 ;16(12): 3684-3695
    Spermidine potentiates anti-tumor immune responses and immunotherapy sensitivity in breast cancer.
    Xinyu Yang, Yaxin Feng, Ruxin Wang, Xin Zeng, Boying Gao, Penghan Huang, Huiping Chen, Wenfeng Zeng.
      Spermidine metabolism influences tumor progression and anti-tumor immunity, thereby affecting treatment sensitivity. However, the precise role and therapeutic potential of spermidine in breast cancer remain unclear. Integrated multi-omics analyses (bulk and single-cell RNA sequencing) revealed a significant positive correlation between intratumoral spermidine abundance and immunophenotypic markers of CD8+ T cell infiltration and activation (GZMB+CD8+ T cells). Immunohistochemical and multiplexed immunohistochemistry validation (IHC/mIHC) demonstrated that breast cancer specimens with elevated spermidine production exhibited increased numbers of activated CD8⁺ T cells. Exogenous supplementation with spermidine promoted CD8⁺ T cell activation directly. Furthermore, supplementing spermidine in vivo promoted anti-tumor immune responses and enhanced sensitivity to anti-PD-1 immunotherapy combined with chemotherapy. Our findings indicate that boosting spermidine metabolism is a promising strategy to reinvigorate CD8⁺ T cell function and improve the efficacy of checkpoint blockade immunotherapy.
    Keywords:  CD8+ T cell; anti-tumor immunity; spermidine; tumor metabolism
    DOI:  https://doi.org/10.7150/jca.113235
  41. Immunotherapy. 2025 Sep 15. 1-19
    Current status of chimeric antigen receptor T cell therapy and its exhaustion mechanism.
    Huiwen Zhang, Juwei Gao, Zipeng Zhang, Bo Zhang.
      With the rapid advancements in oncology, immunology, and molecular biology, immunotherapy has emerged as a cornerstone of anti-tumor treatment, complementing traditional modalities such as surgery, radiotherapy, and chemotherapy. Among the many immunotherapy strategies, adoptive cell therapy (ACT) is the most representative one. A key technology within ACT is chimeric antigen receptor (CAR) T-cell therapy, a precision-targeted treatment that leverages genetic engineering to modify T cells, enabling them to express antigen-specific receptors independent of major histocompatibility complex (MHC) restrictions. In recent years, continuous optimization of CAR-T therapy has been leading to remarkable clinical outcomes in oncology. However, its efficacy is significantly compromised by T-cell exhaustion, characterized by reduced proliferative capacity, attenuated anti-tumor activity, and limited persistence. Notably, CAR-T cell exhaustion is primarily driven by repeated tumor antigen stimulation, sustained autonomous activation of CAR constructs, and the immunosuppressive tumor microenvironment (TME), collectively contributing to disease relapse in hematologic malignancies and limited efficacy in solid tumors. Therefore, it is important to elucidate and inhibit the mechanism of CAR-T cell dysfunction to improve its efficacy. Overcoming these challenges will facilitate the development of CAR-T cells with sustained proliferative potential and tumor clearance.
    Keywords:  CAR-T cell exhaustion; Chimeric antigen receptor T cells; adoptive cell therapy; cancer immunotherapy; tumor immune microenvironment
    DOI:  https://doi.org/10.1080/1750743X.2025.2560798
  42. Cancer Med. 2025 Sep;14(18): e71244
    Metabolic Reprogramming of Cancer Cells and Therapeutics Targeting Cancer Metabolism.
    Jilsy M J Punnasseril, Abdul Auwal, Vinod Gopalan, Alfred King-Yin Lam, Farhadul Islam.
       BACKGROUND: Cancer metabolism is a field focused on the unique alterations in metabolic pathways that occur in cancer cells, distinguishing them from the metabolic processes in normal cells.
    METHODS: An extensive review of the current literature on the metabolic adaptation of cancer cells was carried out in the current study.
    RESULTS: The rapidly proliferating cells require high levels of molecules, such as glucose, amino acids, lipids, and nucleotides, along with increased energy demand (ATP). These requirements are met through alterations in the processes involving glucose, amino acid, lipid, and nucleotide metabolism. Modifications in glucose metabolism in cancer cells involve changes in glucose uptake, glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle. Similarly, alterations in amino acid metabolism in cancer cells relate to upregulated amino acid transport and glutaminolysis. Cancer cells also have increased lipid intake from the extracellular microenvironment, upregulated lipogenesis, and enhanced lipid storage and mobilization from intracellular lipid droplets. These rapidly proliferating cells also achieve their increased demand for nucleotides by changing the expression of enzymes in the salvage and de novo nucleotide pathways. Consequently, these metabolic processes are targets for developing cancer therapeutics. However, it is important to note that the metabolic changes in cancer cells can also contribute to resistance against various cancer therapies.
    CONCLUSION: This review will explore the various ways in which cancer cells reprogram metabolic processes to sustain rapid proliferation and survival. The information presented in this report could help in the therapeutics designed to target them, and the challenges of cancer drug resistance arising from these metabolic adaptations.
    Keywords:  Warburg effect; cancer metabolism; drug resistance; glucose metabolism; nucleotide metabolism; therapeutics
    DOI:  https://doi.org/10.1002/cam4.71244
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