bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2026–01–04
37 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Translational Downregulation of 5' TOP mRNAs During T Cell Exhaustion.
  2. Rewiring T Cell Metabolism to Enhance CAR T Cell Function in Solid Tumor Microenvironments.
  3. Age-independent and targetable transcription factor networks regulating CD8+ T cell senescence in aging humans.
  4. Immuno-oncology approaches to overcome T cell exhaustion in melanoma.
  5. CD8+ T Cell Immunity in HIV Cure and Prevention: Linking Stemness, Spatial Niches, and Emerging Therapeutic Strategies.
  6. Antigen-specific profiling identifies T-bet+ melanoma-specific CD8+ T cells associated with response to neoadjuvant PD-1 blockade.
  7. Metabolomic profiling reveals the potential of fatty acids as regulators of exhausted CD8 T cells during chronic viral infection.
  8. Metabolic reprogramming as a therapeutic target for modulating the Th17/Treg balance in autoimmune diseases: a comprehensive review.
  9. Tissue-resident exhausted and memory CD8+ T cells have distinct ontogeny, function and role in disease.
  10. Optimal avidity of the Immune Synapse and mitochondrial repair trigger asymmetrical cell division and CAR T cell persistence - Review.
  11. Regulatory T Cell Metabolism in Cancer.
  12. Antigen reactivity defines tissue-resident memory and exhausted T cells in tumors.
  13. Uridine depletion impairs CD8⁺ T cell antitumor activity through N-glycosylation.
  14. Above and beyond senescence and CAR T cell: advances and future perspectives.
  15. Nanomedicine-mediated modulation of tumor metabolism for enhanced immunotherapy.
  16. Therapeutic remodeling of the tuberculosis granuloma with 1-methyl-D-tryptophan enhances CD8 + T cell-macrophage interactions.
  17. Epigenetic Suppression of Histone Deacetylase 4 Boosts T Cell Homing via CXCR3 in Lung Cancer: A Step Toward Ultrasound-Guided Immunotherapy.
  18. Generation of T cells with reduced off-target cross-reactivities by engineering co-signalling receptors.
  19. From fat to fate: how aging adipose tissue drives systemic metabolic aging.
  20. Myeloid-Derived CD38 Mediates Age-Related Endometrial Aging Through NAD+ Depletion.
  21. Dimethyl itaconate suppresses dendritic cell and CD8+ T cell responses to halt vitiligo.
  22. Corrigendum to Neutrophil extracellular traps potentiate effector T cells via endothelial senescence in uveitis.
  23. Editorial: The crosstalk between metabolism and inflammation in aging and longevity.
  24. Editorial: Exploring immunometabolism: metabolic pathway and immune response in sepsis.
  25. Perturbation of NAD(P)H metabolism with the LbNOX xenotopic tool extends lifespan and mitigates age-related changes.
  26. IL-7 promotes naïve T cell motility to enable T cell scanning of dendritic cells in the LN.
  27. Rejuvenating the aging gut by targeting senescence.
  28. Autophagic regulation of CD8+ T cell metabolic reprogramming defines acute and latent phases of cytomegalovirus infection in vivo.
  29. Metabolic regulation of regulatory T cells: mechanisms, heterogeneity, and implications in disease.
  30. NKTR-255, a polymer-conjugated IL-15, synergizes with CAR-T cell therapy to activate endogenous anti-tumor immunity and improve tumor control.
  31. The Role and Research Progress of CD8+ T Cells in Sepsis.
  32. The Aryl Hydrocarbon Receptor: A Modulator of Skeletal Muscle Health and Aging.
  33. SIRT3-Mediated Mitochondrial Regulation and Driver Tissues in Systemic Aging.
  34. Senolytic Treatment With Dasatinib and Quercetin Reshapes Influenza-Specific CD8 T Cell Responses During Infection in Aged, Vaccinated Mice.
  35. Engineering IL-21 secretion in T cells using druggable ligand-responsive stabilized domains.
  36. Aging-associated immune signature as a predictor of mortality in end-stage renal disease: results from the longitudinal iESRD study.
  37. BATF2 is a glutamine-responsive tumour suppressor required for type-I interferon-dependent anti-tumour immunity.
  1. bioRxiv. 2025 Dec 16. pii: 2025.12.15.694525. [Epub ahead of print]
    Translational Downregulation of 5' TOP mRNAs During T Cell Exhaustion.
    Erica S Pledger, Navya Ambavaram, Lucas Ferguson, Jamie H D Cate.
      T cell exhaustion is a dysfunctional state that arises during chronic infections and cancer, characterized by impaired effector functions and sustained expression of inhibitory receptors. While transcriptional, epigenetic, and metabolic rewiring have been well documented in exhausted T cells, a comprehensive understanding of how translation is regulated in this state remains incomplete. To address this gap, we performed ribosome profiling and RNA sequencing on exhausted human CD8+ T cells to globally assess translational control. Our analyses reveal a marked repression of 5' terminal oligopyrimidine (TOP) mRNAs during exhaustion. Unexpectedly, we demonstrate that this translational repression occurs despite evidence of elevated mTOR activity in exhausted T cells. These findings uncover a previously unknown layer of translational control in exhausted T cells.
    DOI:  https://doi.org/10.64898/2025.12.15.694525
  2. Pharmaceutics. 2025 Nov 26. pii: 1520. [Epub ahead of print]17(12):
    Rewiring T Cell Metabolism to Enhance CAR T Cell Function in Solid Tumor Microenvironments.
    Alex Wade Song, Xiaotong Song.
      Background/Objectives: Chimeric antigen receptor (CAR) T cells have shown remarkable clinical success in certain blood cancers but remain largely ineffective in solid tumors. A major reason for this limitation is the hostile tumor microenvironment, which restricts oxygen and nutrients while producing toxic metabolites that suppress immune cell activity. This review aims to examine how targeted metabolic reprogramming can overcome these barriers and improve CAR T cell performance. Methods: We evaluated preclinical and translational studies that focused on engineering CAR T cells to resist hypoxia, improve nutrient utilization, reduce metabolic exhaustion, and counteract suppressive metabolites in solid tumors. Results: Emerging strategies include engineering resistance to low oxygen and high lactate, enhancing nutrient uptake through transporter overexpression, and blocking inhibitory pathways such as those driven by adenosine. These approaches improve CAR T cell persistence, memory formation, and cytotoxic function in challenging tumor environments. Conclusions: Integrating metabolic reprogramming with conventional CAR design is essential to unlock the full potential of CAR T therapy against solid tumors. Continued innovation in this area will be critical for translating laboratory advances into effective clinical treatments.
    Keywords:  CAR T cells; adenosine; hypoxia; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3390/pharmaceutics17121520
  3. Cell Rep. 2025 Dec 31. pii: S2211-1247(25)01567-0. [Epub ahead of print]45(1): 116795
    Age-independent and targetable transcription factor networks regulating CD8+ T cell senescence in aging humans.
    Paolo S Turano, Elizabeth Akbulut, Hannah K Dewald, Themistoklis Vasilopoulos, Patricia Fitzgerald-Bocarsly, Utz Herbig, Ricardo Iván Martínez-Zamudio.
      The age-related decline in immunity is accompanied by the accumulation of senescent CD8+ T cells. Using senescent cell isolation coupled with multi-omics profiling, we reveal the transition to senescence to be controlled by chromatin state-specific transcription factor (TF) networks in younger and older donors independent of age. These TF networks mediate widespread enhancer remodeling, repressing cell identity genes while upregulating inflammatory and secretory pathways. Inhibition or downregulation of AP1, KLF5, or RUNX2 modulates the transcriptional output and partially restores the blunted response to stimulation of senescent CD8+ T cells. Senescent CD8+ T cell gene signatures also predict responsiveness to chimeric antigen receptor (CAR)-T cell therapy in diffuse large B cell lymphomas. Overall, our study defines the gene-regulatory mechanisms underlying human CD8+ T cell senescence, highlights TF network perturbation as a viable strategy to manipulate the senescence state, and identifies senescent CD8+ T cell gene signatures as prognostic tools for immunotherapy outcome.
    Keywords:  CAR-T cell; CD8(+) T cells; CP: Immunology; CP: Molecular biology; aging; cellular senescence; chromatin; immunosenescence; immunotherapy; inflammaging; inflammation; transcription factor networks
    DOI:  https://doi.org/10.1016/j.celrep.2025.116795
  4. Semin Oncol. 2025 Dec 02. pii: S0093-7754(25)00146-0. [Epub ahead of print]53(1): 152454
    Immuno-oncology approaches to overcome T cell exhaustion in melanoma.
    Amr Ali Mohamed Abdelgawwad El-Sehrawy, Mohammad Y Alshahrani, Muzdalifa Mejbel Fedwi, Subbulakshmi Ganesan, Zahraa Abbas Al-Khafaji, Vimal Arora, Amrita Pal, Priya Priyadarshini Nayak, Sarvar Islomov, Chou-Yi Hsu.
      Melanoma, a highly aggressive type of skin cancer, has undergone incredible developments in immunotherapy, particularly in modulating T-cell immunity. T cells are essential components of the antitumor immune response and can undoubtedly influence the effectiveness of melanoma treatment. This review will evaluate the roles of the different T cell subsets (CD8+, CD4+, and Tregs) in melanoma immunity. CD8+ T cells are important effectors, as they primarily recognize and kill tumor cells. However, CD8+ T cells are often dysfunctional due to exhaustion driven by chronic antigen exposure and dysfunctional immune checkpoint pathways, specifically PD-1 and CTLA-4. On the other hand, CD4+ T cells, also known as T helper cells, play a crucial role in coordinating both pro- and antitumor immune responses. In contrast to T cells, Tregs, which are often present in the tumor microenvironment, lead to immune suppression through their activity, limiting T cell activity. This review will also examine the mechanisms of T-cell exhaustion, metabolic reprogramming within the tumor microenvironment (TME) of T-cell subsets, and the role of immune checkpoint pathways, such as CTLA-4 and PD-1, in T-cell immunity. Adoptive cell therapies (ACT), specifically Tumor-Infiltrating Lymphocyte (TIL) therapy and Chimeric Antigen Receptor (CAR) T-cell therapy, have shown the ability to rejuvenate T-cells to enhance clinical outcomes. However, several resistance mechanisms and the suppressive TME presents difficulties. Future efforts will focus on combination therapies, metabolic interventions, and novel engineering techniques to overcome barriers to T-cell function exhaustion and T-cell persistence. Evaluating biomarkers associated with early prediction for therapeutic benefit and associated toxicity is important for personalizing a particular treatment. Ultimately, this review highlights the potential of targeting T-cell exhaustion to enhance the effectiveness of T-cell-based therapies in improving outcomes for melanoma patients.
    Keywords:  Exhaustion; Immunity; Immunotherapy; Melanoma; T cell
    DOI:  https://doi.org/10.1016/j.seminoncol.2025.152454
  5. Annu Rev Immunol. 2026 Jan 02.
    CD8+ T Cell Immunity in HIV Cure and Prevention: Linking Stemness, Spatial Niches, and Emerging Therapeutic Strategies.
    Andrea O Papadopoulos, Merantha Moodley, Crystal A Mendoza, Zaza M Ndhlovu.
      The central role of CD8+ T cells in HIV clearance makes them key targets in vaccine and cure strategies. This review examines our evolving understanding of CD8+ T cell-mediated HIV control and its application to curative and preventative interventions. We discuss how CD8+ T cell stemness contributes to protection along the TCF-1 (T cell factor 1) and TOX (thymocyte selection-associated high-mobility group box) axis. We highlight emerging insights, informed by novel clinical trial frameworks, into CD8+ T cell dynamics during acute HIV infection, early therapy, and treatment interruption. Furthermore, we discuss the spatial heterogeneity of CD8+ T cell function in lymphoid tissues, which underscores the antiviral potential of CD8+ T cells during chronic infections and the structural and immunological constraints that limit the clearance of HIV within follicular niches. Looking ahead, we highlight a newly developed CMV-vectored vaccine design targeting HLA-E-restricted CD8+ T cells within the broader context of HLA-E biology, along with advances in HIV chimeric antigen receptor-T cell therapy and HIV-specific T cell receptor engineering.
    DOI:  https://doi.org/10.1146/annurev-immunol-082724-125809
  6. Cancer Cell. 2025 Dec 31. pii: S1535-6108(25)00538-0. [Epub ahead of print]
    Antigen-specific profiling identifies T-bet+ melanoma-specific CD8+ T cells associated with response to neoadjuvant PD-1 blockade.
    Guanning Wang, Daniel Yoon, Ajeya Nandi, Khushboo Patel, Tarek Azar, Justin Kim, Nicholas A Han, Aaron Nickie, Stella Park, Kevin Wang, Patrick Yan, Shraya Divaker, Jennifer Tabita-Martinez, Lydia Giles, Mary Carberry, Jean Christophe Beltra, Mark M Painter, Cecile Alanio, Ravi K Amaravadi, Lynn M Schuchter, Beatriz M Carreno, Gerald P Linette, David E Elder, Robert M Brody, Phyllis Gimotty, John T Miura, Giorgos C Karakousis, Xiaowei Xu, Tara C Mitchell, Alexander C Huang.
      Despite widespread immune profiling in cancer immunotherapy, the antigen-specific responses that drive clinical outcomes remain poorly defined. In a prospective neoadjuvant trial (NCT04013854) of a single-dose anti-PD-1 (nivolumab) in stage III melanoma, we performed antigen-specific profiling of melanoma and viral-specific CD8+ T cells across blood, tumor, and lymph node compartments. Using combinatorial tetramers, we detected melanoma-specific CD8+ T cells in 72% of HLA-A1, -A2, and -A3 patients. These cells displayed distinct phenotypes shaped by tissue and antigen context. Tumor-infiltrating T-bet+ intermediate exhausted CD8+ T cells were strongly associated with pathologic response, while CD39+ terminal exhausted cells marked non-response. T-bet and CD39 expression also stratified responses in uninvolved lymph nodes, suggesting early divergence of therapeutic immune trajectories. Longitudinal profiling revealed that circulating melanoma-specific CD8+ T cell dynamics was antigen-dependent and associated with clinical outcomes. Our findings highlight the clinical value of antigen-specific profiling and identify mechanistic correlates of anti-PD-1 efficacy.
    Keywords:  CD8 T cell reinvigoration; PD-1 blockade; antigen-specific CD8 T cells; biomarker; exhausted T cells; exhausted subsets; immune checkpoint; immune profiling; lymph node; neoadjuvant
    DOI:  https://doi.org/10.1016/j.ccell.2025.12.004
  7. Proc Natl Acad Sci U S A. 2026 Jan 06. 123(1): e2419820122
    Metabolomic profiling reveals the potential of fatty acids as regulators of exhausted CD8 T cells during chronic viral infection.
    Katelynn R Kazane, Lara Labarta-Bajo, Dina R Zangwill, Kalle Liimatta, Fernando Vargas, Kelly C Weldon, Pieter C Dorrestein, Elina I Zúñiga.
      Chronic infections induce CD8 T cell exhaustion, marked by impaired effector function. While intrinsic drivers are well studied, the role of the surrounding metabolic environment in shaping exhausted CD8 T cells (Tex) is less understood. Using untargeted metabolomics and the murine lymphocytic choriomeningitis virus infection model, we investigated systemic metabolite changes following acute vs. chronic viral infections. We identified distinct short-term and persistent metabolite shifts, with the most significant differences occurring transiently during the early phase of the sustained infection. This included nutrient changes that were partially associated with CD8 T cell-induced anorexia and lipolysis. One remarkable observation was the elevation of medium- and long-chain fatty acids (FA) and acylcarnitines during the first week after chronic infection. Consistently, virus-specific CD8 T cells from chronic infection exhibited increased lipid accumulation and uptake compared to their counterparts from acute infection, particularly the stem-like Tex (TexSTEM), which generates TexINT that directly limit viral replication. Notably, only TexSTEM increased oxidative metabolism upon ex vivo FA exposure, while short-term administration of FA during late chronic infection exclusively increased TexSTEM and their mitochondrial potential. The last-mentioned treatment also led to reduced TexINT and enhanced PD-1 across all Tex subsets, which coincided with compromised viral control. Our study offers a valuable resource for investigating the regulatory role of specific metabolites during acute and chronic viral infections and highlights the potential of FA to fine-tune Tex subsets during protracted infections.
    Keywords:  CD8 T cell exhaustion; fatty acids; metabolomics; stem-like cells; viral infection
    DOI:  https://doi.org/10.1073/pnas.2419820122
  8. Front Immunol. 2025 ;16 1687755
    Metabolic reprogramming as a therapeutic target for modulating the Th17/Treg balance in autoimmune diseases: a comprehensive review.
    Yuehong Hu, Qihan Zhao, Haoran Dai, Yadi Wu, Xinyue Tang, Naiqian Zhang, Hanxue Jiang, Hongliang Rui, Baoli Liu.
      The dynamic balance between T helper 17 (Th17) cells and regulatory T (Treg) is the cornerstone of immune homeostasis. Disruption of this equilibrium is closely associated with various autoimmune diseases, including rheumatoid arthritis (RA), multiple sclerosis (MS), and inflammatory bowel disease (IBD). Studies have revealed that metabolic reprogramming, mediated by key metabolic enzymes (including mTOR, HIF-1α, and AMPK) and pathways (such as glycolysis and lipid metabolism), acts as a major regulator of Th17/Treg differentiation and function owing to their distinct metabolic profiles. Metabolic dysregulation may exacerbate immune imbalance by altering the cellular differentiation trajectories and functional states. Although targeting metabolic pathways shows therapeutic promise, current intervention strategies face challenges in terms of specificity and safety. This review systematically combs the mechanisms by which metabolic reprogramming influences the differentiation and function of Th17/Treg cells, as well as the metabolic changes in immune cells of inflammation-related autoimmune diseases. It outlines the progress of the latest metabolism-targeted strategies and focuses on discussing the challenges and prospects regarding the specificity and safety of metabolic interventions.
    Keywords:  Th17/Treg balance; autoimmune diseases; immunometabolism; mTOR; therapeutic target
    DOI:  https://doi.org/10.3389/fimmu.2025.1687755
  9. Nat Immunol. 2025 Dec 29.
    Tissue-resident exhausted and memory CD8+ T cells have distinct ontogeny, function and role in disease.
    Simone L Park, Mark M Painter, Sasikanth Manne, Victor Alcalde, Maura McLaughlin, Matthew A Sullivan, Divij Mathew, Leonel Torres, Yinghui J Huang, David B Reeg, Naomi R Douek, Trenton Campos, Max Klapholz, Maria A Cardenas, Victoria Fang, Shin Foong Ngiow, Wumesh Kc, Rishi R Goel, Amy E Baxter, Jennifer E Wu, Melody Tan, Corbett T Berry, Christoph T Ellebrecht, Huang C Alexander, Emily Papazian, Ying Liu, Karthik Rajasekaran, Robert M Brody, Erica R Thaler, Devraj Basu, Ahmed Diab, Josephine R Giles, E John Wherry.
      The presence of CD8+ T cells coexpressing residency and exhaustion molecules in chronic diseases often correlate with clinical outcomes; however, the relationship between these cells and conventional tissue-resident memory (TRM) cells or exhausted CD8+ T (TEX) cells is unclear. Here we show that chronic antigen stimulation drives development of tissue-resident TEX (TR-TEX) cells that are distinct from TRM cells generated after antigen clearance. TR-TEX and TRM cells are regulated by different transcriptional networks with only TR-TEX cells being Tox-dependent for residency programming. While TEX cells (including TR-TEX) are unable to generate TRM cells after antigen withdrawal, TRM cells differentiate into TEX cells upon chronic antigen exposure. Cell-state-specific transcriptional signatures reveal a selective association of TR-TEX cells with patient responses to immune checkpoint blockade, and only TR-TEX but not TRM cells responded to PD-1 pathway inhibition in vivo. These data suggest that TR-TEX and TRM cells are developmentally divergent cell states that share a tissue-residency program but have distinct roles in disease control.
    DOI:  https://doi.org/10.1038/s41590-025-02352-y
  10. Transplant Cell Ther. 2025 Dec 25. pii: S2666-6367(25)02649-1. [Epub ahead of print]
    Optimal avidity of the Immune Synapse and mitochondrial repair trigger asymmetrical cell division and CAR T cell persistence - Review.
    Jyotishankar Raychaudhuri, Claudio Anasetti.
      Chimeric antigen receptor (CAR) T cell persistence with memory is the current research focus of cancer immunotherapy. The incomplete effect of CAR T cells against tumors results from CAR T cell dysfunction and exhaustion. Asymmetric cell division is an evolutionarily conserved mechanism to maintain mother stem cells during embryonic development, and for immune cells to provide a continuous supply of diverse populations to fight infections and cancer. CAR T cells use ACD to determine their fate during the first mitotic division after interaction with its target, creating a pool of memory CAR T cells which can be recalled to be effector cells during tumor relapse, necessarily to offset the diminished ability of exhausted CAR T cells in controlling the tumor. Affinity of the CAR T - target cell immune synapse and mitochondrial dynamics regulate ACD. We review the literature regarding CAR T cell persistence, exhaustion, and mechanisms of reversing exhaustion. Subsequently, we present a hypothesis linking mitophagy to CAR T cell exhaustion, modulation of which may be clinically relevant in the treatment of cancers with CAR T cells.
    Keywords:  Asymmetric cell division; CAR T cells; Exhaustion; Memory; Mitophagy; Persistence; T cells
    DOI:  https://doi.org/10.1016/j.jtct.2025.12.988
  11. Immunology. 2025 Dec 28.
    Regulatory T Cell Metabolism in Cancer.
    Keywan Mortezaee.
      Regulatory T cells (Tregs) display metabolic fitness to adopt tumour microenvironment (TME), characterized by hypoxia, acidity and metabolic depletion/competition, in order to impair anti-tumour immunity and allow metastasis. Tregs and other TME immune cells interact metabolically, with glycolysis supporting proliferation of Tregs along with cancer cells and CD8+ T cells and a basal oxidative phosphorylation (OXPHOS) promoting Treg and CD8+ T cell activity. Lactate is a glycolysis byproduct that its accumulation creates acidosis within TME, and its uptake provides a fuel source for Treg activity and fosters their persistence in the hypoxic TME. Itaconate and hypoxic TME increase succinate accumulation, but they take complex roles on Tregs and T cells. Hypoxia and hypoxia inducible factor-1 (HIF-1) activity induce lactate release and Treg recruitment/accumulation via stimulating glycolysis path and extracellular adenosine aggregation. Knockout of HIF-1α although reduces lactate, it secondarily induces OXPHOS to fulfil Treg immunosuppressive function. FOXP3 is stabilized by mitochondrial transcription factor A (Tfam) and induces Treg CD36 and OXPHOS, which can be disturbed by nucleus accumbens-associated protein 1 (NAC1). Liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK) although induce FOXP3 stability and OXPHOS in Tregs, their activities downregulate programmed death-1 (PD-1) in such cells. OXPHOS augmentation (by α-ketoglutarate [αKG]) or suppression (by metformin) disrupt Treg metabolism. Finally, indoleamine 2,3-dioxygenase (IDO) seems to affect Tregs and can be a promising target in advanced immunotherapy naïve cancer patients. The focus of this review is to describe Treg metabolic regulators/connectome and opportunities they bring about in cancer therapy.
    Keywords:  adenosine; aryl hydrocarbon receptor (AHR); glycolysis; hypoxia inducible factor (HIF); lactate; liver kinase B1 (LKB1); metformin; oxidative phosphorylation (OXPHOS); regulatory T cell (Treg); α‐Ketoglutarate (αKG)
    DOI:  https://doi.org/10.1111/imm.70096
  12. Nat Immunol. 2025 Dec 29.
    Antigen reactivity defines tissue-resident memory and exhausted T cells in tumors.
    Thomas N Burn, Jan Schröder, Luke C Gandolfo, Maleika Osman, Elanor N Wainwright, Enid Y N Lam, Keely M McDonald, Rachel B Evans, Shihan Li, Daniel Rawlinson, Lachlan Dryburgh, Ali Zaid, Zoltan Maliga, Dominick Schienstock, Philippa Meiser, Hyun Jae Lee, Hongjin Lai, Marcela L Moreira, Pirooz Zareie, Louis H-Y Lee, Lutfi Huq, Susan N Christo, Justine J W Seow, Keith A Ching, Stéphane M Guillaume, Kathy Knezevic, Simone L Park, Maximilien Evrard, Jason Waithman, Thomas Gebhardt, Scott N Mueller, Georgina E Riddiough, Marcos V Perini, Simon C H Tsao, Terence P Speed, Peter K Sorger, Sherene Loi, Francis R Carbone, Stephanie Gras, Timothy S Fisher, Bas J Baaten, Mark A Dawson, Laura K Mackay.
      CD8+ T cells are an important weapon in the therapeutic armamentarium against cancer. While CD8+CD103+ T cells with a tissue-resident memory T (TRM) cell phenotype are associated with favorable prognoses, the tumor microenvironment also contains dysfunctional exhausted T (TEX) cells that exhibit a variety of TRM-like features. Here we deconvolute TRM and TEX cells across human cancers, ascribing markers and gene signatures that distinguish these populations and enable their functional distinction. Although TRM cells have superior functionality and are associated with long-term survival post-tumor resection, they are not associated with responsiveness to immune checkpoint blockade. Tumor-associated TEX and TRM cells are clonally distinct, with the latter comprising tumor-independent bystanders and tumor-specific cells segregated from cognate antigen. Intratumoral TRM cells can be forced toward an exhausted fate when chronic antigen stimulation occurs, indicating that the presence or absence of continuous antigen exposure within the microenvironment is the key distinction between tumor-associated TEX and TRM populations. These results highlight unique functions for TRM and TEX cells in tumor control, underscoring the need for distinct strategies to harness these populations for cancer therapies.
    DOI:  https://doi.org/10.1038/s41590-025-02347-9
  13. Cell Metab. 2025 Dec 29. pii: S1550-4131(25)00530-3. [Epub ahead of print]
    Uridine depletion impairs CD8⁺ T cell antitumor activity through N-glycosylation.
    Jianbiao Xiao, Zhiyang Li, Yi Ding, Kejin Zhu, Zhihao Zheng, Yaowei Zhang, Jiawen Weng, Feifei Wang, Yuqin Zhang, Sisi Zeng, Minxing Qiu, Zhaowen Zhang, Zhizhang Wang, Li Liang.
      Immune checkpoint blockade (ICB) faces limitations owing to high cost and restricted efficacy. This study identifies SNX17 as a key mediator of ICB resistance. Elevated SNX17 correlates with poor anti-PD-1 response in humans and mice. SNX17 deletion in tumor cells inhibits tumor growth via CD8+ T cell-dependent mechanisms. SNX17 reduces uridine in the tumor microenvironment (TME), suppressing IFN-γ and upregulating PD1 in CD8+ T cells. Exogenous uridine shows antitumor efficacy comparable to anti-PD-1/PD-L1 in low-SNX17 tumors and overcomes resistance in high-SNX17 models. Uridine enhances CD8+ T cell function by promoting CD45 N-glycosylation and LCK phosphorylation. Mechanistically, SNX17 stabilizes RUNX2, promoting UPP1 transcription and uridine degradation in the TME. These findings position SNX17 as an ICB response biomarker and nominate uridine as a cost-effective immunotherapeutic strategy.
    Keywords:  CD8+ T cell; N-glycosylation; SNX17; UPP1; checkpoint blockade; immunotherapy resistance; uridine
    DOI:  https://doi.org/10.1016/j.cmet.2025.11.016
  14. Front Immunol. 2025 ;16 1701655
    Above and beyond senescence and CAR T cell: advances and future perspectives.
    Rebeca Rosas-Campos, Scarlet Arceo-Orozco, Ana Sandoval-Rodriguez, Jose Alejandro Madrigal, Juan Armendariz-Borunda.
      Cellular senescence is a complex biological process that contributes to the progression of age-related diseases. Senescent cells accumulate over time and secrete proinflammatory factors that disrupt tissue homeostasis and promote chronic diseases. Initially created for cancer immunotherapy, chimeric antigen receptor (CAR) T cell therapy has recently been repurposed at the preclinical level to eliminate senescent cells by recognizing senescence-associated surface markers. Recent preclinical studies have demonstrated the feasibility of anti-uPAR and anti-NKG2D CAR T cell-based approaches for eliminating senescent cells in preclinical models of fibrosis, metabolic disorders, and natural aging, resulting in reduced fibrotic burden, improved metabolic parameters, and enhanced tissue function. However, several challenges remain in their clinical applicability, including the identification of specific and universal senescence markers, potential off-target effects, and long-term safety concerns. Additionally, immunosenescence, an age-related decline in immune function, poses challenges for CAR T cell therapy in elderly patients. This review discusses recent advancements in CAR T cell therapy for senescence clearance, highlighting key molecular targets, preclinical findings, and future research directions. Despite their promise, a significant translational gap persists, and further research is required to improve the specificity, efficacy, and readiness for future human clinical trials.
    Keywords:  CAR T cell; aging-related diseases; immunotherapy; senescence; targeting senescent cells
    DOI:  https://doi.org/10.3389/fimmu.2025.1701655
  15. J Control Release. 2025 Dec 30. pii: S0168-3659(25)01201-5. [Epub ahead of print] 114587
    Nanomedicine-mediated modulation of tumor metabolism for enhanced immunotherapy.
    Yanjun Liu, Dongqi Sun, Wenshi Li, Zhixiao Zhang, Ce Li, Xiaofang Che, Shenwu Zhang.
      Immunotherapy has emerged as a transformative approach in cancer treatment. However, its efficacy remains limited in many cases. A key factor contributing to this limitation is metabolic reprogramming within the tumor microenvironment (TME), which suppresses immune cell function and promotes tumor progression. Recently, nanotechnology-based approaches have opened new ways to modulate tumor metabolism and enhance immunotherapy. This review outlines nanoscale strategies aimed at reprogramming tumor metabolism to potentiate antitumor immunity. We begin by discussing the rational design of immune-metabolic nanoregulators, along with key immunometabolic pathways and their regulatory mechanisms. Next, nanotechnology strategies for targeted metabolic intervention at the cellular and microbial levels, as well as the metabolic characteristics of TME are systematically summarized. Furthermore, we highlight recent advances in nanomedicine-based metabolic regulators and evaluate their potential for clinical translation, addressing both opportunities and challenges.
    Keywords:  Cancer immunotherapy; Metabolism regulation; Nanotherapeutics; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.jconrel.2025.114587
  16. bioRxiv. 2025 Oct 04. pii: 2025.10.02.680083. [Epub ahead of print]
    Therapeutic remodeling of the tuberculosis granuloma with 1-methyl-D-tryptophan enhances CD8 + T cell-macrophage interactions.
    Erin F McCaffrey, Alea C Delmastro, Bindu Singh, Annu Devi, Nadia A Golden, Shabaana A Khader, Michael Angelo, Deepak Kaushal, Smriti Mehra.
      Granulomas, the hallmark of tuberculosis (TB) disease, can both restrict Mycobacterium tuberculosis (Mtb) dissemination and impede its clearance. Recent studies indicate that indoleamine 2,3-dioxygenase (IDO1), an immunosuppressive metabolic enzyme, limits infiltration of activated T cells and can contribute to TB disease progression. Treatment with 1-methyl-D-tryptophan (D-1MT), a small molecule inhibitor that restores mTOR signaling, has been shown to improve immune responses Mtb -infected rhesus macaques. Here, we investigated the impact of D-1MT treatment on TB granuloma architecture using 30-plex high-dimensional issue imaging in rhesus macaques. By spatially mapping 13 distinct cell populations, we found D-1MT treatment corresponded with significantly increased infiltration CD8 + T cells into granulomas compared to untreated controls. Notably, these CD8 + T cells expressed markers of cell proliferation and cytotoxicity. D-1MT enhanced CD8 + T cell infiltration throughout the granuloma, with particularly pronounced effects in the myeloid core, where we observed significantly enhanced spatial interactions between macrophages and CD8 + , but not CD4 + T cells. Our results demonstrate that: (i) effective intra-granulomatous Mtb control is associated with the close spatial proximity between CD8 + T cells and macrophages, a feature less abundant in uncontrolled pulmonary TB; (ii) IDO1 induction blocks CD8 + T cell infiltration and reduces T cell activation and proliferation; and (iii) therapeutic strategies, including D-1MT, that improve intra-granulomatous killing hold strong translational potential.
    Significance statement: Our understanding of immune mechanisms within the TB granuloma has advanced greatly with the advent of high-resolution single cell multiplexed imaging. Using such imaging, we show that TB granulomas in rhesus macaques, a highly translational model of human TB pathology, are characterized by IDO1-mediated immunoregulation. Early pharmacologic restoration of mTOR signaling via D-1MT treatment can reduce IDO1 enzymatic activity and facilitate the recruitment and function of CD8 + T cells within the granulomas. These findings reveal specific mechanisms exploited by Mtb to maintain intra-granuloma persistence and underscore immune responses. Future vaccine and therapeutic design should consider these immunoregulatory features to achieve better control of Mtb infection.
    DOI:  https://doi.org/10.1101/2025.10.02.680083
  17. Cancer Biother Radiopharm. 2025 Dec 24.
    Epigenetic Suppression of Histone Deacetylase 4 Boosts T Cell Homing via CXCR3 in Lung Cancer: A Step Toward Ultrasound-Guided Immunotherapy.
    Lingqiong Lan, Yi Wang, Liming Guo, Yongxin Xie.
      Background: Lung cancer is the biggest reason of cancer-correlated death worldwide, owing primarily to immune evasion and poor response to current immunotherapies. Objective: The aim of this work was focused on the immunomodulatory effect of histone deacetylase 4 (HDAC4) in tumor immunological milieu, specifically CD8+ T cell trafficking. Methods: Quantitative RT-PCR, immunofluorescence labeling, and FISH tests were used to determine HDAC4 and CXCR3 expression and location in lung cancer tissues. Flow cytometry assessed CD8+ T cell function, and histological analysis revealed tumor development. Results: Our results showed that HDAC4 was highly overexpressed in lung tumor samples, and it was associated with advanced clinical stage, lymph node metastases, and a worse overall survival rate. HDAC4 decreased CXCR3 expression, affecting CD8+ T cell infiltration and effector function. HDAC4 knockdown increased CD8+ T cell cytotoxicity, whereas CXCR3 inhibition reversed this effect. HDAC4 expression predicted poor survival with a ROC AUC of 0.78. SB939 treatment raised CXCR3 expression by 2.4 times and CD8+ infiltration by 39%. Conclusion: These findings point to HDAC4 as a crucial epigenetic regulator of immune cell trafficking in lung cancer. Given the growing interest in ultrasound-assisted medication delivery and immunological priming, our findings point to HDAC4 as a viable therapeutic target in ultrasound-guided immunomodulatory methods for lung cancer.
    Keywords:  CD8+ T cells; HDAC4; cytotoxicity; lung cancer; tumor microenvironment; ultrasound-assisted therapy
    DOI:  https://doi.org/10.1177/10849785251403850
  18. Nat Biomed Eng. 2026 Jan 02.
    Generation of T cells with reduced off-target cross-reactivities by engineering co-signalling receptors.
    Jose Cabezas-Caballero, Anna Huhn, Mikhail A Kutuzov, Violaine Andre, Alina Shomuradova, Bas W A Peeters, Geraldine M Gillespie, P Anton van der Merwe, Omer Dushek.
      Adoptive T cell therapy using T cells engineered with novel T cell receptors (TCRs) targeting tumour-specific peptides is a promising immunotherapy. However, these TCR-T cells can cross-react with off-target peptides, leading to severe autoimmune toxicities. Current efforts focus on identifying TCRs with reduced cross-reactivity. Here we show that T cell cross-reactivity can be controlled by the co-signalling molecules CD5, CD8 and CD4, without modifying the TCR. We find the largest reduction in cytotoxic T cell cross-reactivity by knocking out CD8 and expressing CD4. Cytotoxic T cells engineered with a CD8→CD4 co-receptor switch show reduced cross-reactivity to random and positional scanning peptide libraries, as well as to self-peptides, while maintaining their on-target potency. Therefore, co-receptor switching generates super selective T cells that reduce the risk of lethal off-target cross-reactivity and offers a universal method to enhance the safety of T cell immunotherapies for potentially any TCR.
    DOI:  https://doi.org/10.1038/s41551-025-01563-w
  19. Biogerontology. 2025 Dec 27. 27(1): 30
    From fat to fate: how aging adipose tissue drives systemic metabolic aging.
    Haiyan Lin, Hongyu Li, Qiang Tang.
      Aging adipose tissue is a consequence of organismal aging and an "amplifier" that drives systemic metabolic disorders. This review proposes the conceptual framework of the "aging metabolic amplifier", systematically explaining how aging adipose tissue reshapes the microenvironment of distant organs through its secretory profile, thereby linking obesity, diabetes, cardiovascular diseases, and neurodegenerative diseases. The concept of the "aging metabolic amplifier" emphasizes the important role of senescent adipocytes in systemic metabolic dysfunction, and systematically elaborates on their heterogeneous characteristics, autonomous and non-autonomous changes, as well as their mechanisms in ectopic lipid deposition, cardiovascular diseases, and cognitive decline. Currently, specific intervention strategies-such as activating the thermogenic program, eliminating senescent cells, regulating autophagy, and improving the microenvironment- have been proposed, providing potential therapeutic directions for delaying aging and related metabolic diseases.
    Keywords:  Adipose tissue; Aging; Inflammation; Intervention strategy; Metabolism
    DOI:  https://doi.org/10.1007/s10522-025-10376-y
  20. Aging Cell. 2026 Jan;25(1): e70356
    Myeloid-Derived CD38 Mediates Age-Related Endometrial Aging Through NAD+ Depletion.
    Lun Hua, Luting Liu, Dengfeng Gao, Lulu Ma, Xianyang Jin, Liuyong Lu, Shangbo Tian, Xuemei Jiang, Chao Jin, Bin Feng, Lianqiang Che, Shengyu Xu, Yan Lin, Long Jin, Yong Zhuo, Mingzhou Li, De Wu.
      Against the backdrop of the global trend toward delayed childbearing, elucidating the mechanisms underlying uterine aging has emerged as a critical biomedical priority for addressing age-related implantation failure. Through unbiased global metabolomic profiling of peri-implantation uteri across different ages in mice, we identified nicotinamide adenine dinucleotide (NAD+) depletion as a hallmark metabolic feature of endometrial aging. Single-cell RNA sequencing further revealed an expansion of senescent stromal cell populations, which was accompanied by a decline in NAD+ levels. Supplementation with NAD+ precursors alleviated age-related stromal senescence and endometrial dysfunction, thereby restoring the uterus' implantation competence. Mechanically, we demonstrate that CD38 derived from myeloid serves as a principal driver of uterine NAD+ depletion; this process accelerates stromal senescence and impairs uterine receptivity. These findings establish CD38 as a central physiological integrator that links NAD+ metabolism to uterine function and highlight it as a promising target for rejuvenation strategies aimed at improving reproductive outcomes in women of advanced maternal age.
    Keywords:  CD38; NAD+; endometrial aging; macrophage
    DOI:  https://doi.org/10.1111/acel.70356
  21. BMC Med. 2025 Dec 29. 23(1): 698
    Dimethyl itaconate suppresses dendritic cell and CD8+ T cell responses to halt vitiligo.
    Yinghan Wang, Yuhan Chen, Jingjing Ma, Linxuan Wu, Pan Kang, Jianru Chen, Pengran Du, Wei Wu, Xinju Wang, Kaiqiao He, Yuqi Yang, Sen Guo, Weinan Guo, Ling Liu, Zhe Jian, Tianwen Gao, Shuli Li, Chunying Li.
       BACKGROUND: Although dendritic cell (DC)- and CD8+ T cell-mediated autoimmunity is critical for destroying melanocytes in vitiligo, treatment options remain limited by the absence of therapies that cotarget both cell types.
    METHODS: We first evaluated the association between the immunoregulatory metabolite itaconate and disease development, by determining human vitiligo serum itaconate levels and monitoring depigmentation progression in Acod1 knockout (KO) mice with endogenous itaconate deficiency. We further evaluated the therapeutic efficacy of the itaconate derivative, dimethyl itaconate (DI) in mice and assessed its effects on cutaneous infiltration and the functional properties of DCs and CD8+ T cells in vivo and ex vivo. The gene signatures and signaling pathways involved in DI-treated CD8+ T cells were also assessed.
    RESULTS: We observed an elevation of circulating itaconate in vitiligo patients, whereas itaconate deficiency accelerated depigmentation in Acod1 KO mice after vitiligo induction. The administration of DI halted vitiligo development and promoted repigmentation, with elevated circulating itaconate levels, increased melanocyte counts, and decreased cutaneous CD8+ T cell densities. Mechanistically, DI dampened CD8+ T cell activation (CD69), effector function (Interferon-γ, IFN-γ), cytotoxicity (Gzmb), proliferation, and proinflammatory gene expression (Csf1, Ifitm1, CD49a, NKG2D, and NKG2A), partly by suppressing the Janus kinase (JAK)‒STAT pathway. Moreover, DI-treated mice exhibited reduced cutaneous DC infiltration, as well as fewer DCs with mature and migratory phenotypes.
    CONCLUSIONS: Our findings identify DI as a metabolite-derived small molecule that protects against autoimmune injury by cotargeting DC and CD8+ T cell responses, thereby demonstrating a promising therapeutic strategy and providing a foundation for treating vitiligo and other cell-specific autoimmune diseases.
    Keywords:  Autoimmune disease; CD8+ T cell; Dendritic cell; Dimethyl itaconate; JAK-STAT pathway; Vitiligo
    DOI:  https://doi.org/10.1186/s12916-025-04512-1
  22. JCI Insight. 2026 Jan 09. pii: e202699. [Epub ahead of print]11(1):
    Corrigendum to Neutrophil extracellular traps potentiate effector T cells via endothelial senescence in uveitis.
    Zuoyi Li, Zhuang Li, Yunwei Hu, Yanyan Xie, Yuxun Shi, Guanyu Chen, Jun Huang, Zhiqiang Xiao, Wenjie Zhu, Haixiang Huang, Minzhen Wang, Jianping Chen, Xiaoqing Chen, Dan Liang.
      
    DOI:  https://doi.org/10.1172/jci.insight.202699
  23. Front Endocrinol (Lausanne). 2025 ;16 1734527
    Editorial: The crosstalk between metabolism and inflammation in aging and longevity.
    Sandeep Kumar, Ahmed Elmansi, Mohamed Noureldein, James Harper.
      
    Keywords:  aging; cell death; inflammation; longevity; metabolism; mitochondrial stress; senescence
    DOI:  https://doi.org/10.3389/fendo.2025.1734527
  24. Front Med (Lausanne). 2025 ;12 1758108
    Editorial: Exploring immunometabolism: metabolic pathway and immune response in sepsis.
    Yuan Yuan, Lulong Bo, Ruoxi Zhang, Feng Chen.
      
    Keywords:  editorial; immune response; immunometabolism; metabolic pathway; sepsis
    DOI:  https://doi.org/10.3389/fmed.2025.1758108
  25. Sci Adv. 2026 Jan 02. 12(1): eady0628
    Perturbation of NAD(P)H metabolism with the LbNOX xenotopic tool extends lifespan and mitigates age-related changes.
    Shweta Yadav, Xingxiu Pan, Shengxi Li, Paige LaRae Martin, Ngoc Hoang, Kejin Chen, Aditi Karhadkar, Jatin Malhotra, Austin L Zuckerman, Subrata Munan, Markus K Klose, Lin Wang, Valentin Cracan, Andrey A Parkhitko.
      Aging involves widespread metabolic dysregulation, including a decline in total nicotinamide adenine dinucleotide (NAD) levels. While NAD precursor supplementation elevates total NAD levels, it does not reveal tissue-specific effects of an altered NADH [reduced form of NAD+ (oxidized NAD)]/NAD+ balance. To address this, we generated transgenic Drosophila expressing the genetically encoded xenotopic enzyme LbNOX, which converts NADH to NAD+. LbNOX expression modulated both NAD(H) and NADP(H) (reduced form of NAD phosphate) metabolites in a sex-dependent manner and rescued neuronal cell death induced by mutant αB-crystallin-associated reductive stress. We demonstrate that tissue-specific targeting of redox NAD metabolism shows distinct outcomes: Muscle-specific LbNOX expression confers stronger protection against paraquat-induced oxidative stress than whole-body expression, emphasizing tissue-dependent redox sensitivity. Notably, LbNOX expression in nonneuronal tissues restored youthful sleep patterns in aged flies. Together, these findings establish LbNOX as an efficient xenotopic tool for in vivo redox manipulation and reveal tissue- and sex-specific NAD(P)H mechanisms underlying aging, stress resilience, and sleep regulation, providing a framework for NAD-based interventions in aging.
    DOI:  https://doi.org/10.1126/sciadv.ady0628
  26. Cytokine. 2025 Dec 29. pii: S1043-4666(25)00252-2. [Epub ahead of print]198 157105
    IL-7 promotes naïve T cell motility to enable T cell scanning of dendritic cells in the LN.
    Janie R Byrum, Kimberly A Morrissey, David J Torres, Sreenivasa Rao Oruganti, Judy L Cannon.
      IL-7 is a key regulator of naïve T cell homeostasis including T cell development, survival, and proliferation. IL-7 is highly expressed in lymph nodes (LNs), and we investigated the potential for IL-7 to drive naïve T cell movement in LNs. We show that IL-7 can mediate high speed T cell movement in vitro and in LNs. Downstream of IL-7R, T cell motility requires JAK1/3 and STAT5 activation, but mTOR signaling is not required. Using computational modeling and imaging of T cell motion in lymph nodes through two photon microscopy, we find that IL-7R-mediated motility accounts for T cell localization near DCs in the LN, suggesting that IL-7 can regulate naive T cell contacts with DCs. These data demonstrate a novel role for the IL-7/IL-7R pathway in controlling rapid T cell motility, showing that IL-7/IL-7R mediated T cell motion can facilitate efficient T cell-DC interactions in the LN.
    Keywords:  Chemokines; Interleukin-7; JAK/STAT signaling; T cell migration
    DOI:  https://doi.org/10.1016/j.cyto.2025.157105
  27. Nat Aging. 2026 Jan 02.
    Rejuvenating the aging gut by targeting senescence.
    Marina Kolesnichenko.
      
    DOI:  https://doi.org/10.1038/s43587-025-01045-3
  28. Front Cell Infect Microbiol. 2025 ;15 1673229
    Autophagic regulation of CD8+ T cell metabolic reprogramming defines acute and latent phases of cytomegalovirus infection in vivo.
    Hui Liu, Xiaobing Liu, Wai Ho Oscar Yeung, Jiang Liu, Kevin Tak Pan Ng, Kwan Man.
      Understanding the immunoregulatory mechanism during cytomegalovirus (CMV) infection may help to combat CMV reactivation in immunocompromised or immunosuppressed individuals. Here we developed a CMV infection model in immunocompetent Sprague Dawley (SD) rats with Priscott strain and explored the cross-talk between autophagic dynamics and metabolism alterations in CD8+ T cells post infection. We previously found that primary CMV infection induced a remarkable increase of CD8+ T cells which reached the peak around week 3 and returned to pre-inoculation status since week 6 post viral infection. In this study, our results demonstrated that the autophagic activity of CD8+ T cells was augmented at week 3 while decreased at week 6, which was closely associated with the up- (week 3 and 4) or down-regulation (since week 6) of metabolic markers ENTPD1 and SLC27A2. Furthermore, the in vitro study showed that the levels of these metabolic markers in rat splenocytes were modulated by autophagy inhibitors and enhancers. Our study indicated that the dynamic alterations of autophagy exerted a critical role in regulating the metabolic adaptation of CD8+ T cells during CMV infection process, and provides an ideal animal model for further research on the pathological mechanisms based on CMV latency.
    Keywords:  CD8+ T cells; autophagic dynamics; cytomegalovirus; metabolism; sprague-dawley rats
    DOI:  https://doi.org/10.3389/fcimb.2025.1673229
  29. Front Immunol. 2025 ;16 1729690
    Metabolic regulation of regulatory T cells: mechanisms, heterogeneity, and implications in disease.
    Feven Getachew, Junhui Hu, Mehdi Benamar.
      Regulatory T (Treg) cells are essential for maintaining immune tolerance, preventing autoimmune responses, and supporting tissue repair. Tregs employ a flexible and diverse metabolic program that includes glycolysis, oxidative phosphorylation (OXPHOS), fatty acid oxidation, and lipid metabolism compared to conventional T cells, which largely rely on glycolysis to fuel their proliferation and function. This flexibility allows Tregs to adapt in different tissue environments while sustaining their suppressive activity. Thymic-derived (tTregs), peripheral (pTregs), and induced (iTregs) exhibit distinct metabolic profiles that influence their stability, proliferation, and suppressive capacity. These metabolic pathways are controlled by key regulators such as mTOR, LKB1, and Foxp3, while environmental cues, including nutrient availability, hypoxia, and microbiota-derived metabolites, further shape Treg function. Dysregulation of these pathways can compromise tolerance and contribute to immune-mediated diseases, chronic infections, cancer, and metabolic disorders. In this mini review, we summarize recent insights into the heterogeneity of Treg metabolism, highlighting how metabolic reprogramming underpins their immunoregulatory roles. We also explore therapeutic opportunities for targeting Treg metabolism and discuss future directions leveraging single-cell and spatial technologies to map context-specific metabolic programs in vivo.
    Keywords:  Foxp3; diseases; immune tolerance; metabolism; regulatory T cells
    DOI:  https://doi.org/10.3389/fimmu.2025.1729690
  30. bioRxiv. 2025 Dec 15. pii: 2025.12.11.693768. [Epub ahead of print]
    NKTR-255, a polymer-conjugated IL-15, synergizes with CAR-T cell therapy to activate endogenous anti-tumor immunity and improve tumor control.
    W Sam Nutt, Mitchell G Kluesner, Emma Bingham, Ekram Gad, Dani Miller, Victor Zepeda, Andrew J Snyder, Sydney A Marsh, Shannon M Liudahl, Mari Hoffman, Lillian LeBlanc, Madeleine E Volfbeyn, Sarah M Garrison, Megha Sarvothama, Kevin C Barry, Mark B Headley, Mario Marcondes, Shivani Srivastava.
      CAR-T cells have yet to show widespread efficacy in solid tumors due in part to their poor persistence and loss of function in the tumor microenvironment. Further, heterogenous expression of most CAR target antigens in solid tumors can lead to escape of antigen-null tumors that resist CAR-T killing. Strategies to cooperatively boost both CAR-T and endogenous anti-tumor immunity could curb tumor escape and may be critical for achieving durable efficacy in cancer patients. NKTR-255 is a polymer-conjugated IL-15 with extended half-life that can boost endogenous T and NK cells, as well as CD19 CAR-T activity in B cell malignancies. However, whether NKTR-255 is sufficient to overcome CAR-T dysfunction in the suppressive solid tumor microenvironment, and how NKTR-255 and CAR-Ts together re-shape endogenous anti-tumor immunity, is not known. Using an autochthonous mouse model of ROR1 + lung adenocarcinoma, we show that NKTR-255 significantly boosted accumulation, reduced exhaustion, and improved function of tumor-infiltrating CAR-T cells. Compared with NKTR-255 or CAR-T treatment alone, combination of NKTR-255 and CAR-T therapy synergistically increased tumor-infiltrating CD11b + cytotoxic NK cells, activated dendritic cells, and endogenous tumor-specific T cells that preserved a PD-1 + Tcf1 + stem-like phenotype. Consequently, NKTR-255 and CAR-T combination therapy induced complete elimination of ROR1 + tumor and significantly improved survival, with enhanced tumor control dependent on activity of both CAR-Ts and endogenous T cells. Altogether, our data suggest that combining NKTR-255 with CAR-T therapy is a promising strategy to enhance both CAR-T and endogenous anti-tumor immunity to promote coordinated control of aggressive tumors.
    DOI:  https://doi.org/10.64898/2025.12.11.693768
  31. Biomedicines. 2025 Nov 27. pii: 2912. [Epub ahead of print]13(12):
    The Role and Research Progress of CD8+ T Cells in Sepsis.
    Xianwen Wang, Qihang Huang, Zhihong Zuo, Zhanwen Wang, Lina Zhang, Zhaoxin Qian.
      Sepsis is a systemic inflammatory response syndrome induced by infection, characterized by high morbidity and mortality, and responsible for over 11 million deaths worldwide annually. Recent studies have demonstrated that immune dysfunction represents a core element in the pathophysiology of sepsis, in which cluster of differentiation 8-positive (CD8+) T cells, as key executors of cellular immunity, play a critical role in immune dysregulation. This review systematically elaborates on the quantitative changes, functional status, and molecular regulatory mechanisms of CD8+ T cells in sepsis, including abnormalities in metabolic reprogramming, cell death pathways, transcriptional regulation, and intercellular communication. Additionally, it explores potential therapeutic strategies targeting CD8+ T cells, such as immune checkpoint modulation, cell death intervention, and metabolic regulation, and offers an outlook on future research directions, aiming to provide novel insights for immunotherapy in sepsis.
    Keywords:  CD8+ T cells; immune checkpoints; immune dysfunction; metabolic reprogramming; sepsis
    DOI:  https://doi.org/10.3390/biomedicines13122912
  32. Biochimie. 2025 Dec 29. pii: S0300-9084(25)00317-7. [Epub ahead of print]
    The Aryl Hydrocarbon Receptor: A Modulator of Skeletal Muscle Health and Aging.
    Keon Wimberly, Terence E Ryan.
      Skeletal muscle is fundamental to human health, serving as the primary effector of movement and a central regulator of systemic metabolism. Age-related declines in muscle mass and mitochondrial function contribute to frailty, metabolic dysfunction, and loss of independence in older adults. While these changes are often attributed to reduced physical activity, chronic inflammation, and impaired regenerative capacity, emerging evidence implicates environmental and metabolic sensing pathways in muscle degeneration. The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor best known for mediating responses to environmental pollutants such as dioxins, has recently been recognized as a key regulator of endogenous metabolic and redox processes. AHR activation occurs not only through xenobiotic exposure but also via endogenous ligands derived from tryptophan metabolism-including kynurenine and indole derivatives-whose levels rise in aging, chronic kidney disease (CKD), and other pollutant exposures. Sustained AHR activation in skeletal muscle has been shown to impair mitochondrial oxidative phosphorylation, promote proteolysis, and disrupt neuromuscular junction integrity, linking AHR signaling to muscle pathology. Experimental studies in rodent models demonstrate that pharmacologic or genetic inhibition of AHR can preserve muscle mass, mitochondrial function, and regenerative capacity. This review summarizes the molecular biology of the AHR, its emerging roles in skeletal muscle physiology and pathology, and the growing experimental toolkit for interrogating its function. Understanding how AHR signaling integrates environmental, metabolic, and aging cues may reveal new therapeutic opportunities to preserve skeletal muscle health and physical function across the lifespan.
    Keywords:  AHR; aging; frailty; hydrocarbon; muscle
    DOI:  https://doi.org/10.1016/j.biochi.2025.12.012
  33. Genes (Basel). 2025 Dec 15. pii: 1497. [Epub ahead of print]16(12):
    SIRT3-Mediated Mitochondrial Regulation and Driver Tissues in Systemic Aging.
    Kate Šešelja, Ena Šimunić, Sandra Sobočanec, Iva I Podgorski, Marija Pinterić, Marijana Popović Hadžija, Tihomir Balog, Robert Belužić.
      Mitochondrial dysfunction is a defining hallmark of aging that connects redox imbalance, metabolic decline, and inflammatory signaling across organ systems. The mitochondrial deacetylase SIRT3 preserves oxidative metabolism and proteostasis, yet its age-related decline transforms metabolically demanding organs into sources of pro-senescent cues. This review synthesizes evidence showing how SIRT3 loss in select "driver tissues"-notably liver, adipose tissue, vascular endothelium, bone-marrow macrophages, and ovary-initiates systemic aging through the release of cytokines, oxidized metabolites, and extracellular vesicles. We discuss molecular routes and mediators of senescence propagation, including the senescence-associated secretory phenotype (SASP), mitochondrial-derived vesicles, and circulating mitochondrial DNA, as well as sex-specific modulation of SIRT3 by hormonal and intrinsic factors. By integrating multi-tissue and sex-dependent data, we outline a framework in which SIRT3 activity defines the mitochondrial threshold separating local adaptation from systemic aging spread. Targeting SIRT3 and its NAD+-dependent network may offer a unified strategy to restore mitochondrial quality, dampen chronic inflammation, and therefore recalibrate the aging dynamics of an organism.
    Keywords:  NAD+ metabolism; SIRT3; aging drivers; extracellular vesicles; inflammaging; mitochondrial acetylation; senescence; sex differences; systemic aging
    DOI:  https://doi.org/10.3390/genes16121497
  34. Aging Cell. 2026 Jan;25(1): e70345
    Senolytic Treatment With Dasatinib and Quercetin Reshapes Influenza-Specific CD8 T Cell Responses During Infection in Aged, Vaccinated Mice.
    Andreia N Cadar, Blake L Torrance, Sofie A Fischler, Darlene A Djaba, Zena Haddad, Dominique E Teskey, Nagaraju Marka, Kelsey A Gorgei, Erica C Lorenzo, Laura Haynes, Jenna M Bartley.
      Older adults are disproportionately affected by infectious diseases like influenza (flu) due to immune declines and poor vaccine responses. Senolytics have been shown to improve various age-related conditions and positively influence infection outcomes, yet their potential to enhance vaccine responses has not yet been explored. Here, we evaluated the potential of senolytic combination Dasatinib (D) and Quercetin (Q) treatment prior to influenza vaccination to potentiate immune responses in aged mice. D + Q had minimal impact on overall vaccination and flu outcomes in vaccinated mice, including viral load and lung pathology. However, we observed altered CD8 T cell immunodominance and increased serum total PR8 (whole flu) IgG antibodies in D + Q treated vaccinated aged mice during infection. These findings reveal a new aspect of immunomodulation with senolytics.
    Keywords:  T cells; aging; infection; influenza; senolytic; vaccination
    DOI:  https://doi.org/10.1111/acel.70345
  35. Sci Rep. 2025 Dec 27.
    Engineering IL-21 secretion in T cells using druggable ligand-responsive stabilized domains.
    Dong Hyun Kim, Seo Jin Lee, Taeyoung Ahn, Hyung-Young Kim, Kyungsu Kim, Hyungseok Seo.
      Cytokine-based immunotherapies face challenges due to systemic toxicity and uncontrolled cytokine release. To enable precise control, we developed a druggable ligand-dependent IL-21 secretion system using destabilization domains (DDs). ER50 and DHFR facilitated ligand-responsive IL-21 secretion, with ER50 providing the most sustained regulation. Structural analysis revealed that N-terminal fusion improved IL-21 receptor binding, while C-terminal fusion weakened interactions. In primary T cells, IL-21 secretion promoted T stem-like (Tscm) cell differentiation, enhancing persistence for adoptive cell therapy. This system enables reversible, tunable cytokine control, offering a safer and more flexible approach for engineered T cell therapies.
    Keywords:  Destabilization domain (DD); IL-21; Immunotherapy; Ligand-dependent regulation; T cell engineering
    DOI:  https://doi.org/10.1038/s41598-025-32677-5
  36. Immun Ageing. 2025 Dec 29.
    Aging-associated immune signature as a predictor of mortality in end-stage renal disease: results from the longitudinal iESRD study.
    Kai-Hsiang Shu, TienYu Owen Yang, Graham Pawelec, Feng-Jung Yang, Wan-Chuan Tsai, Yu-Sen Peng, Shih-Ping Hsu, Yi-Fang Chuang, Yen-Ling Chiu.
       BACKGROUND: Accelerated immune aging has been implicated in patients with end-stage kidney disease, but a detailed examination of immune profiles correlated with long-term outcomes for these individuals has never been performed. Therefore, we conducted a prospective observational study ("Immunity in end-stage renal disease", iESRD) to investigate the effects of immune aging on mortality among these patients. An exploratory panel of immune cell subsets was analyzed by flow cytometry at baseline (neutrophils, CD3-negative lymphocytes, CD4 and CD8 T cell differentiation stages, and three subsets of monocytes). Immune cell distribution patterns were identified through data-driven principal component analysis (PCA).
    RESULTS: A total of 409 hemodialysis patients (mean age 61.7 years, range 29.5-89.1) were enrolled and followed for three years, during which 75 deaths occurred. Compared with survivors, deceased patients displayed features of more advanced immune aging, which was also correlated with older chronological ages. For individual subset, a higher level of CD8 naïve cells and a lower level of CD4 effector memory cells at baseline were associated with lower mortality. For comprehensive immune signature, principal component analysis identified three major patterns, with PC3-characterized by loss of naïve T cells and enrichment of effector memory T cells and non-classical monocytes-strongly associated with age and independently corelated to all-cause (hazard ratio [HR] 1.31, P = 0.02) and cardiovascular mortality (HR 1.49, P = 0.04). A trend toward mortality risk in higher CMV IgG titer individuals was also observed. Importantly, PC3 retained prognostic value independent of chronological age, suggesting that immune dysfunction may contribute to excess mortality in dialysis patients.
    CONCLUSIONS: Our results confirmed that an age-associated immune signature was associated with all-cause and cardiovascular mortality in hemodialysis patients. This immune monitoring may be extended to other chronic disease populations associated with aging.
    Keywords:  Hemodialysis; Lymphocyte; Monocyte; Mortality; Principal component analysis
    DOI:  https://doi.org/10.1186/s12979-025-00554-4
  37. Nat Commun. 2025 Dec 29.
    BATF2 is a glutamine-responsive tumour suppressor required for type-I interferon-dependent anti-tumour immunity.
    Wang Gong, Hülya F Taner, Yuesong Wu, Yumin He, Xingwu Zhou, Zaiye Li, Xin Hu, Charisse Ursin, Kala Chand Debnath, Kohei Okuyama, Qiang Hu, Christopher R Donnelly, Felipe Nör, Chamila D Perera, Emily Bellile, Arash Yunesi, Zhiqian Zhai, Mei Zhao, Wanqing Cheng, Zackary R Fitzsimonds, Luke Broses, Jiaqian Li, Shadmehr Demehri, Deepak Nagrath, Gregory T Wolf, Andrew G Sikora, Yanbao Yu, Haitao Wen, Lei Wei, Steven B Chinn, Jeffrey N Myers, Shizuo Akira, Yuying Xie, James J Moon, Yu Leo Lei.
      Recent evidence highlights the significance of a new type of tumour suppressors, which are not frequently mutated but inhibited by metabolic cues in cancers. Here, we identify BATF2 as a tumour suppressor whose expression is epigenetically silenced by glutamine in Head and Neck Squamous Cell Carcinomas (HNSCC). BATF2 correlates with type-I interferon and Th1 signatures in human HNSCC, with correlation coefficients even stronger than those of the positive control, STING. The phosphorylation of BATF2 at serine 227 promotes the oligomerization of STING. BATF2 deficiency or high glutamine levels result in higher oxygen consumption rates and metabolic profiles unfavorable for type-I interferon production. An isocaloric glutamine-rich diet abolishes STING-mediated effector cell expansion in tumours, weakening STING agonist-induced tumour control. Cancer cell-specific BATF2 expression promotes an Id2-centered T-cell effector signature, reduces T-cell exhaustion, and triggers spontaneous HNSCC rejection in a type-I interferon-dependent fashion. Utilizing syngeneic subcutaneous, orthotopic, and 24-week-long cigarette smoke carcinogen-induced HNSCC models, we demonstrate that host Batf2 deficiency results in increased infiltration of CD206+ myeloid cells and reduced effector CD8+ T-cells, accelerating the initiation of cancers. Overall, we reveal a tumour suppressor BATF2 whose loss is mediated by unique metabolic cues in the TME and drives cancer immune escape.
    DOI:  https://doi.org/10.1038/s41467-025-68027-2
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