bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–06–29
twenty-six papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Mitochondrial Regulation of CD8⁺ T Cells: Mechanisms and Therapeutic Modulation.
  2. The prostacyclin receptor PTGIR is a NRF2-dependent regulator of CD8+ T cell exhaustion.
  3. The Molecules with Double-Edged Sword Roles in T Cell: An Implication for Adoptive T Cell Therapy.
  4. T cell exhaustion: Focus on molecular pathways.
  5. Gene-regulatory programs that specify age-related differences during thymocyte development.
  6. Lipids rewire T cell exhaustion.
  7. Tumour-associated vasculature in T cell homing and immunity: opportunities for cancer therapy.
  8. Memory matters: T cell phenotype shapes CAR T cell fate.
  9. Functional characterisation of CD8+ T cells mobilised with acute supramaximal high-intensity interval exercise: implications for immune surveillance.
  10. Recharging aged-CAR with NAD+ to boost immunotherapy.
  11. Highly cross-reactive and competent effectors dominate the CD8+ T cell response in Trypanosoma cruzi infection.
  12. Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants.
  13. Targeting CD4+ T Cell Glucose Metabolism: A Novel Immunotherapeutic Approach for Type 1 Diabetes.
  14. Prolonged but finite antigen presentation promotes reversible defects of "helpless" memory CD8+ T cells.
  15. The next innovations in chimeric antigen receptor T cell immunotherapies for cancer.
  16. Therapeutic potential of NRF2 activating drug RTA-408 in suppressing T cell effector responses and inflammatory bowel disease.
  17. Gut microbiota-specific T cells induce neuroinflammation through molecular mimicry.
  18. WTAP Accelerates Exhaustion of CD8+ T Cells and Progression of Hepatocellular Carcinoma by Promoting m6A Modification and Translation of PD1 mRNA.
  19. Nucleic acid-based nanogels with "offensive and defensive"effects for enhanced chemo-immunotherapy.
  20. Regulation of actin cytoskeletal dynamics in T cell development and function.
  21. Beneficial role of GZMK+CD8+ T cells in neurodegeneration.
  22. Hallmarks of stem cell aging.
  23. The aging immune system and all-cause mortality in older americans: differences across sex and race/ethnicity.
  24. Human cDC1 enhance cytotoxic function of CD226+ terminally exhausted tumor-infiltrating lymphocytes.
  25. CD38-Targeting Peptide Vaccine Ameliorates Aging-Associated Phenotypes in Mice.
  26. Mitochondria-targeted NAD+/O2 co-delivery interpenetrating network hydrogel for respiratory chain restoration and osteoarthritis therapy.
  1. Adv Sci (Weinh). 2025 Jun 23. e03095
    Mitochondrial Regulation of CD8⁺ T Cells: Mechanisms and Therapeutic Modulation.
    Xu Chen, Pei Lin, Ye Lu, Jiarong Zheng, Yunfan Lin, Zihao Zhou, Li Cui, Xinyuan Zhao.
      Mitochondria are integral to the regulation of CD8+ T cell function, critically influencing processes such as activation, differentiation, and long-term persistence during immune responses. Emerging evidence highlights the detrimental impact of mitochondrial dysfunction on CD8+ T cell activity, contributing to immune exhaustion and impairing both antitumor and antiviral immunity. This underscores the importance of understanding and modulating mitochondrial dynamics to optimize T cell-based immunotherapies. In this review, a comprehensive and in-depth analysis of the essential mitochondrial processes-including biogenesis, redox homeostasis, and metabolic reprogramming is provided-that govern CD8+ T cell function and are intricately linked to their therapeutic potential. The current strategies aimed at enhancing mitochondrial function in CD8+ T cells are also examined, focusing on both metabolic reprogramming and mitochondrial-targeted interventions. Despite these promising approaches, several significant challenges remain, such as achieving selective targeting, addressing mitochondrial plasticity, and mitigating off-target effects. Overcoming these obstacles will be crucial to improving the clinical efficacy and safety of mitochondrial modulation therapies. As the understanding of mitochondrial dynamics within CD8+ T cells continues to evolve, there is growing potential to leverage these insights to improve immune-based therapies across a range of diseases, including cancer and viral infections.
    Keywords:  CD8⁺ T cells; T cell exhaustion; immunotherapy; metabolic reprogramming; mitochondrial dynamics
    DOI:  https://doi.org/10.1002/advs.202503095
  2. Nat Immunol. 2025 Jun 27.
    The prostacyclin receptor PTGIR is a NRF2-dependent regulator of CD8+ T cell exhaustion.
    Michael S Dahabieh, Lisa M DeCamp, Brandon M Oswald, Susan M Kitchen-Goosen, Zhen Fu, Matthew Vos, Shelby E Compton, Joseph Longo, Nicole M Foy, Kelsey S Williams, Abigail E Ellis, Amy Johnson, Ibukunoluwa Sodiya, Michael Vincent, Hyoungjoo Lee, Chen Yao, Tuoqi Wu, Ryan D Sheldon, Connie M Krawczyk, Russell G Jones.
      CD8+ T cell exhaustion (Tex) limits immune control of cancer, but the underlying molecular drivers are unclear. In the present study, we identified the prostaglandin I2 (prostacyclin) receptor PTGIR as a cell-intrinsic regulator of T cell exhaustion. Transcriptomic profiling of terminally exhausted (Ttex) CD8+ T cells revealed increased activation of the nuclear factor erythroid 2-related factor 2 (NRF2) oxidative stress response pathway. Enhancing NRF2 activity (by conditional deletion of Kelch-like ECH-associated protein 1 (KEAP1)) boosts glutathione production in CD8+ T cells but accelerates terminal exhaustion. NRF2 upregulates PTGIR expression in CD8+ T cells. Silencing PTGIR expression enhances T cell effector function (that is, interferon-γ and granzyme production) and limits Ttex cell development in chronic infection and cancer models. Mechanistically, PTGIR signaling impairs T cell metabolism and cytokine production while inducing transcriptional features of Tex cells. These findings identify PTGIR as a NRF2-dependent immune checkpoint that regulates balance between effector and exhausted CD8+ T cell states.
    DOI:  https://doi.org/10.1038/s41590-025-02185-9
  3. Crit Rev Oncol Hematol. 2025 Jun 17. pii: S1040-8428(25)00198-2. [Epub ahead of print] 104810
    The Molecules with Double-Edged Sword Roles in T Cell: An Implication for Adoptive T Cell Therapy.
    Marziyeh Samiee, Saeedeh Salehi, Leila Mohamed Khosroshahi, Tahereh Soltantoyeh.
      Immune checkpoints have traditionally been viewed as inhibitory molecules that downregulate immune cell activity, acting as a safeguard against excessive immune responses. In chronic infections and cancer, however, these checkpoints serve as barriers that can inhibit effective immune responses, thereby reducing pathological consequences. Over the years, researchers have explored immune checkpoint blockade through antibody-based therapies and have sought to delete these molecules in adoptive T cell therapy to enhance T cell function and proliferation. However, emerging research suggests that immune checkpoint deletion may not always be advantageous; these molecules appear to play complex roles in supporting T cell functions like metabolism, cytotoxicity, proliferation and persistence. Some of them might have roles in T cell differentiation into subsets like memory cells. This article delves into the evolving understanding of immune checkpoint molecules, such as PD-1, TIM-2, A2aR, 2B4 and EP2, highlighting their nuanced roles in immune regulation and implications for immunotherapy. We proposed that these molecules should be viewed as a double-edged sword and regulated with greater caution, taking into account their lesser-known roles and other interacting factors.
    Keywords:  Immune checkpoint blockade; T cell therapy; immunotherapy; solid tumors
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.104810
  4. Pathol Res Pract. 2025 Jun 11. pii: S0344-0338(25)00274-2. [Epub ahead of print]272 156081
    T cell exhaustion: Focus on molecular pathways.
    Qiucai Dang.
      T cell exhaustion developed as a safeguard against excessive immune damage, but it can impair the immune system's ability to combat infections and cancer. Scientists are focused on developing strategies to revitalize exhausted T cells and enhance immune responses. Research indicates that the state of T cells within tumors is closely linked to the outcomes of immune checkpoint blockade therapy. This manuscript reviews the complete molecular pathways concerning exhaustion triggered in cells due to transcription factor metabolic dysfunction, microRNA regulation, and the cytokine environment. T cell exhaustion is characterized by increased transcription of Nr4a1, Nr4a2, Nr4a3, and immune checkpoint molecules. Additionally, these exhausted T cells present altered metabolic profiles, with impaired glucose metabolism and mitochondrial dysfunction contributing to impairments in their effective antitumor responses. This energy-deprived and dysfunctional state significantly limits their capacity to proliferate and exert cytotoxic effects against cancer cells. This paper will discuss the potential therapeutic strategies to overcome these obstacles.
    Keywords:  Immune checkpoint blockade; Malignancies; NR4A; T cell exhaustion
    DOI:  https://doi.org/10.1016/j.prp.2025.156081
  5. Cell Rep. 2025 Jun 25. pii: S2211-1247(25)00674-6. [Epub ahead of print]44(7): 115903
    Gene-regulatory programs that specify age-related differences during thymocyte development.
    Divya Ganapathi Sankaran, Hongya Zhu, Viviana I Maymi, Isabel M Forlastro, Ya Jiang, Nathan Laniewski, Kristin M Scheible, Brian D Rudd, Andrew Grimson.
      T cell development is fundamental to immune system establishment, but how this development changes with age remains poorly understood. Here, we construct a transcriptional and chromatin accessibility atlas of T cell developmental programs in neonatal and adult mice, revealing the ontogeny of divergent gene-regulatory programs and their link to age-related differences. Specifically, we identify a gene module that diverges with age from the earliest stages of genesis and includes programs that govern the effector response and cell cycle. Moreover, we reveal that neonates possess more accessible chromatin during early thymocyte development, likely establishing poised gene expression programs that manifest later in thymocyte development. Finally, we leverage this atlas, employing a CRISPR-based perturbation approach coupled with single-cell RNA sequencing readout, to uncover a conserved transcriptional regulator, Zbtb20, that contributes to age-dependent differences in T cell development. In summary, our study defines gene-regulatory programs that regulate age-specific differences in T cell development.
    Keywords:  CD8(+) T cell; CP: Immunology; HSCs; RNA-seq; T cell development; adults; double negative; double positive; immune; neonates; single positive
    DOI:  https://doi.org/10.1016/j.celrep.2025.115903
  6. Nat Immunol. 2025 Jun 27.
    Lipids rewire T cell exhaustion.
    Marie-Elen Tuchel, Annette Oxenius.
      
    DOI:  https://doi.org/10.1038/s41590-025-02177-9
  7. Nat Rev Immunol. 2025 Jun 27.
    Tumour-associated vasculature in T cell homing and immunity: opportunities for cancer therapy.
    Evripidis Lanitis, Melita Irving, George Coukos.
      The formation of new blood vessels - known as angiogenesis - is essential for the growth and spread of solid tumours. It is promoted by the hypoxic conditions that develop in growing tumours and drive the expression of pro-angiogenic growth factors by tumour cells and various stromal cells. However, the tumour-associated vasculature (TAV) generated by angiogenesis is abnormal and is a key barrier to T cell entry into tumours. Moreover, the TAV creates a hostile microenvironment owing to an accumulation of suppressive immune cells, hypoxic and acidic conditions, and high interstitial pressure, which all limit the function and survival of effector T cells. Here, we present the mechanisms of T cell migration into tumours, including via high endothelial venules, and the importance of tertiary lymphoid structures, which function as privileged sites for antigen presentation, activation and co-stimulation of T cells, for mounting effective antitumour immunity. We describe how the tumour vasculature limits antitumour T cell responses and how T cell responses could be improved by therapeutic targeting of the TAV. In particular, the use of combination therapies that aim to normalize tumour blood vessels, favourably reprogramme endogenous immunity, and support T cell trafficking, function and persistence will be key to improving clinical responses.
    DOI:  https://doi.org/10.1038/s41577-025-01187-w
  8. Mol Ther. 2025 Jun 25. pii: S1525-0016(25)00462-9. [Epub ahead of print]
    Memory matters: T cell phenotype shapes CAR T cell fate.
    Francesco Di Meo.
      
    DOI:  https://doi.org/10.1016/j.ymthe.2025.06.011
  9. Clin Transl Immunology. 2025 ;14(6): e70037
    Functional characterisation of CD8+ T cells mobilised with acute supramaximal high-intensity interval exercise: implications for immune surveillance.
    Anna Strömberg, Mirko Mandić, Brennan J Wadsworth, Sebastian Proschinger, Seher Alam, Lisa Mj Eriksson, Laura Barbieri, Eric Rullman, Helene Rundqvist.
       Objectives: The beneficial influence of exercise on outcomes such as infection control and cancer prevention has been attributed partly to the immune system response during physical exertion. CD8+ T cells play a crucial role in immune surveillance, and in this study, we performed an in-depth analysis of the impact of supramaximal high-intensity exercise (HIIT) on CD8+ T-cell dynamics and function, which are currently lacking in the literature.
    Methods: CD8+ T cells obtained from healthy human subjects before and after 3 × 30 s of HIIT were analysed ex vivo for viability and expansion properties, metabolic function using SeaHorse, IFN-gamma release using EliSpot, phenotype using RNA-seq and flow cytometry, and cytotoxic capacity by co-culture with HEK293T cells.
    Results: Exercise led to a threefold increase in CD8+ T-cell count, and CD8+ T cells obtained after exercise had a more cytotoxic profile. Post-exercise CD8+ T cells had a lower glycolytic capacity than pre-exercise cells, and incubation of pre-exercise CD8+ T cells with post-exercise serum replicated this metabolic shift, suggesting a systemic effect of exercise on CD8+ T-cell metabolism. Importantly, CD8+ T cells maintained their viability and expansion properties despite the metabolic challenges induced by exercise. Functionally, post-exercise CD8+ T cells showed increased release of IFN-gamma and an enhanced unspecific cell killing capacity as demonstrated by co-culture with the immortalised cell line HEK293T.
    Conclusion: The pronounced increase in the total number of circulating CD8+ T-cells with an increased cytotoxic capacity suggests a potential improvement in immune surveillance after acute HIIT.
    Keywords:  CD8+ T cells; cytotoxicity; exercise; flow cytometry; immune surveillance; metabolism
    DOI:  https://doi.org/10.1002/cti2.70037
  10. Trends Cancer. 2025 Jun 25. pii: S2405-8033(25)00152-9. [Epub ahead of print]
    Recharging aged-CAR with NAD+ to boost immunotherapy.
    Gaofeng Fan, Yuetong Wang, Ruoning Wang.
      Impaired cellular metabolism contributes to the age-related decline in T cell function, undermining the response to immunotherapy in older patients with cancer. In a recent study, Hope et al. report that a reduction in intracellular NAD+ levels compromises metabolic fitness and drives immunosenescence. Notably, restoring NAD+ levels can reverse age-related chimeric antigen receptor (CAR)-T deterioration, suggesting a promising 'metabolic immunotherapy' that widely benefits older patients with cancer.
    Keywords:  CAR-T therapy; NAD(+); aging; metabolic immunotherapy
    DOI:  https://doi.org/10.1016/j.trecan.2025.06.009
  11. J Immunol. 2025 Jun 16. pii: vkaf107. [Epub ahead of print]
    Highly cross-reactive and competent effectors dominate the CD8+ T cell response in Trypanosoma cruzi infection.
    Molly E Bunkofske, Pradyot Dash, Walid Awad, Paul G Thomas, Rick L Tarleton.
      CD8+ T cells are key effectors in immune control of Trypanosoma cruzi infection. Within C57BL/6 mice, the T. cruzi-specific CD8+ T cell response is largely comprised of T cells recognizing trans-sialidase (TS)- and mucin-encoded epitopes. Despite their immunodominance, these epitope-specific CD8+ T cells are entirely dispensable for immune control. In a screen for epitopes inducing "protective" CD8+ T cells, we uncovered a high level of cross-reactivity within the TSKb20-specific CD8+ T cell response. This cross-reactivity was driven by the TSKb20 epitope itself and not the infection. TCR sequencing defined key characteristics of the TSKb20 repertoire including biased TRBV12-1/12-2 and TRBJ2-1/2-7 gene usage and a highly dominant CDR3β motif. The dispensability of the TSKb20 response in the control of T. cruzi infection along with the broad reactivity of this T cell population prompted us to assess the relative effector capacity of TSKb20 T cells at the site of reinfection. Similar to other activated CD8+ T cells at the site, TSKb20-specific CD8+ T cells expressed transcriptional patterns associated with effector function, suggesting that TSKb20 T cells are capable and likely participants in parasite control. These results indicate that broad TCR reactivity does not compromise the ability of TSKb20-specific T cells to develop into phenotypically functional effectors. Additionally, the failure to identify individual parasite epitopes capable of driving a protective CD8+ T cell response challenges the paradigm that individual T. cruzi epitopes, including highly immunodominant ones, are critical to or exploitable for the potent recognition of T. cruzi-infected host cells and infection control.
    Keywords:   Trypanosoma cruzi ; CD8+ T cells; TCR; cross-reactive epitopes; immunodominant
    DOI:  https://doi.org/10.1093/jimmun/vkaf107
  12. Cell Rep Med. 2025 Jun 19. pii: S2666-3791(25)00283-6. [Epub ahead of print] 102210
    Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants.
    Or-Yam Revach, Angelina M Cicerchia, Ofir Shorer, Claire A Palin, Boryana Petrova, Seth Anderson, Baolin Liu, Joshua Park, Lee Chen, Arnav Mehta, Samuel J Wright, Niamh McNamee, Aya Tal-Mason, Giulia Cattaneo, Payal Tiwari, Hongyan Xie, Johanna M Sweere, Li-Chun Cheng, Natalia Sigal, Elizabeth Enrico, Marisa Miljkovic, Shane A Evans, Ngan Nguyen, Mark E Whidden, Ramji Srinivasan, Matthew H Spitzer, Yi Sun, Tatyana Sharova, Aleigha R Lawless, William A Michaud, Martin Q Rasmussen, Jacy Fang, Jeannette R Brook, Feng Chen, Xinhui Wang, Cristina R Ferrone, Donald P Lawrence, Ryan J Sullivan, David Liu, Uma M Sachdeva, Debattama R Sen, Keith T Flaherty, Robert T Manguso, Lloyd Bod, Manolis Kellis, Genevieve M Boland, Keren Yizhak, Jiekun Yang, Naama Kanarek, Moshe Sade-Feldman, Nir Hacohen, Russell W Jenkins.
      CD38, an ecto-enzyme involved in NAD+ catabolism, is highly expressed in exhausted CD8+ T cells and has emerged as an attractive target to improve response to immune checkpoint blockade (ICB) by blunting T cell exhaustion. However, the precise role(s) and regulation of CD38 in exhausted T cells and the efficacy of CD38-directed therapeutic strategies in human cancer remain incompletely defined. Here, we show that CD38+CD8+ T cells are induced by chronic TCR activation and type I interferon stimulation and confirm their association with ICB resistance in human melanoma. Disrupting CD38 restores cellular NAD+ pools and improves T cell bioenergetics and effector functions. Targeting CD38 restores ICB sensitivity in a cohort of patient-derived organotypic tumor spheroids from explanted melanoma specimens. These results support further preclinical and clinical evaluation of CD38-directed therapies in melanoma and underscore the importance of NAD+ as a vital metabolite to enhance those therapies.
    Keywords:  3D microfluidic culture; CD38; NAD(+); PD-1; T cell exhaustion; cytokines; ex vivo; immunotherapy; organotypic tumor spheroids
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102210
  13. Biomolecules. 2025 May 27. pii: 770. [Epub ahead of print]15(6):
    Targeting CD4+ T Cell Glucose Metabolism: A Novel Immunotherapeutic Approach for Type 1 Diabetes.
    Ying Niu, Na Wang, Leiying Qiao, Zhenxia Huang, Gaojing Jing, Songbo Fu, Xulei Tang.
      Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the destruction of insulin-producing β-cells. Emerging evidence highlights the pivotal role of CD4+ T cell subsets in driving T1D pathogenesis, where their activation, proliferation, and differentiation are tightly regulated by glucose metabolic pathways. Recent studies demonstrate that key enzymes and intermediates of glycolysis, OXPHOS, and other metabolic pathways critically modulate CD4+ T cell functions. In this review, we discuss how glucose metabolic pathways affect CD4+ T cell differentiation and functions. We also summarize the latest progress regarding glucose metabolism intervention to control the T cell immune response in T1D, with the expectation of providing new insights into T1D progression and treatment.
    Keywords:  CD4+ T cell; Th1; Th17; Tregs; glucose metabolism; targeted treatment; type 1 diabetes
    DOI:  https://doi.org/10.3390/biom15060770
  14. Immunity. 2025 Jun 23. pii: S1074-7613(25)00246-8. [Epub ahead of print]
    Prolonged but finite antigen presentation promotes reversible defects of "helpless" memory CD8+ T cells.
    Verena van der Heide, Gabriel Laghlali, Bennett Davenport, Beatrice Cubitt, Vladimir Roudko, Daniel Choo, Kevin Jhun, Etienne Humblin, Abishek Vaidya, Krista Angeliadis, Travis Dawson, Glaucia Furtado, Alice O Kamphorst, Michael Schotsaert, Rafi Ahmed, Juan Carlos de la Torre, Dirk Homann.
      Generation of functional memory CD8+ T cells typically requires engagement of CD4+ T cells. In certain acutely resolving infections, however, effector and memory CD8+ T (Tmem) cell formation appears impervious to the lack of CD4+ T cell help. Nevertheless, "helpless" CD8+ Tmem cells may respond poorly upon rechallenge. The origin and long-term fate of helpless CD8+ Tmem cells remain incompletely understood. Using multiple host-pathogen systems, we demonstrate that helpless effector CD8+ T cell differentiation was largely normal, with a paradoxical accumulation of TCF1hi "memory precursors." However, exposure of CD8+ T cells to residual antigen impaired the development of the Tmem pool. These defects eventually resolved over time, with full restoration of memory potential and recall capacity. Our findings identify prolonged antigen presentation under helpless conditions as an essential determinant for transient CD8+ Tmem cell dysfunction in acutely resolving infections and highlight plasticity within the Tmem compartment, with implications for vaccination strategies and beyond.
    Keywords:  CD4(+) T cell help; CD8(+) T cell memory; Listeria monocytogenes; acute infection; influenza A virus; lymphocytic choriomeningitis virus; vaccinia virus; “helpless” memory
    DOI:  https://doi.org/10.1016/j.immuni.2025.05.025
  15. Cytotherapy. 2025 May 23. pii: S1465-3249(25)00720-0. [Epub ahead of print]
    The next innovations in chimeric antigen receptor T cell immunotherapies for cancer.
    Kusala Anupindi, Julia Malachowski, Isabella Hodson, Daniel Zhu, Carl H June, Bruce L Levine.
      Chimeric antigen receptor (CAR) T cell therapy has transformed cancer treatment and the field of immunotherapy. Although CAR T cell therapy has demonstrated considerable clinical success for the treatment of B cell malignancies, expanding its therapeutic efficacy and accessibility for other hematological malignancies and solid tumors remains a challenge. Key limitations include manufacturing constraints and therapeutic hurdles, such as CAR T cell persistence, proliferation, tumor trafficking and treatment-related toxicities. To overcome the unique challenges associated with CAR T cell therapy, novel technological advancements in CAR design, delivery, and T cell functionality can be leveraged. This review will explore three innovative approaches: gene editing and silencing, armoring strategies and in vivo CAR gene delivery. These approaches are all aimed at enhancing the accessibility and therapeutic efficacy of CAR T cell therapy in hematological malignancies.
    Keywords:  CAR T cell therapy; T cell; advanced therapies; cancer immunotherapy; cellular therapy; gene therapy
    DOI:  https://doi.org/10.1016/j.jcyt.2025.05.010
  16. J Immunol. 2025 Jun 16. pii: vkaf117. [Epub ahead of print]
    Therapeutic potential of NRF2 activating drug RTA-408 in suppressing T cell effector responses and inflammatory bowel disease.
    Debolina Dasgupta, Aprajita Tripathi, Rachel Griffard-Smith, Nandakumar Yellapu, Poojaben Dhorajiya, Kalyani Pyaram.
      RTA-408, also known as Omaveloxolone, is an FDA-approved drug for treating Friedrich's Ataxia, a neurological disorder. It is a triterpenoid compound that activates nuclear factor erythroid 2-related factor 2 (NRF2), a key regulator of cellular redox balance. In this study, we explored the impact of RTA-408 on T cells and evaluated its therapeutic potential in inflammatory bowel disease (IBD). In vitro activation of murine and human T cells in the presence of RTA-408 resulted in suppressed proliferation, reduced expression of IFN-γ, cytotoxic granules and IL-17, but enhanced frequency of Foxp3+ Treg cells. Treatment of Nrf2-deficient T cells with RTA-408 revealed that while the reduction in CD69 expression, IL-2, and IFN-γ levels is NRF2-dependent, the suppression of T cell proliferation and granzyme B/perforin expression occurs independently of NRF2. In vivo administration of RTA-408 alleviated the disease severity in DSS-induced colitis mice by decreasing colonic T cell counts and their inflammatory cytokine production. Additionally, ex vivo treatment of T cells from IBD patients with RTA-408 reduced their expansion and IL-17 expression. Transcriptomic and metabolic analyses revealed that RTA-408 reduces glycolysis and mitochondrial respiration in T cells and reprograms their metabolism towards pentose phosphate pathway and glutaminolysis. Our findings highlight the potential of RTA-408 as a modulator of T cell homeostasis, metabolism, and inflammation, supporting its repurposing for inflammatory diseases like IBD.
    Keywords:  Nrf2 activating drugs; antioxidation; cytokines; immunometabolism; ulcerative colitis
    DOI:  https://doi.org/10.1093/jimmun/vkaf117
  17. Nat Rev Immunol. 2025 Jun 24.
    Gut microbiota-specific T cells induce neuroinflammation through molecular mimicry.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-025-01201-1
  18. Mediators Inflamm. 2025 ;2025 6217272
    WTAP Accelerates Exhaustion of CD8+ T Cells and Progression of Hepatocellular Carcinoma by Promoting m6A Modification and Translation of PD1 mRNA.
    Rong Li, Shunle Li, Hua Li, Bingli Liu, Zimu Wang, Huanqin Lei, Yuting Li, Lijuan Jia, Junhui Li, Hongwei Lu, Meng Xu.
      The N6-methyladenosine (m6A) methylase WTAP has been identified as a proto-oncogene in multiple cancers, including hepatocellular carcinoma (HCC). Interestingly, although WTAP expression does not differ between normal liver and HCC tissues or across different stages of HCC, patients with higher WTAP expression exhibit significantly shorter median survival times (MSTs). Here, we found that WTAP was upregulated in tumor-infiltrating CD8+ T cells, which were more enriched in HCC patients compared to the controls. HCC patients also displayed higher PD1 levels and a greater proportion of exhausted CD8+ T cells (TCF+ PD1+). Moreover, WTAP promoted PD1 expression and suppressed the proliferation and immune activity of CD8+ T cells. In the co-culture system, WTAP-overexpressing CD8+ T cells enhanced the malignancy of HCC cells. Notably, WTAP silencing further augmented the boosting effect of PD1 silencing on CD8+ T cell immune activity and strengthened its inhibitory effect on HCC cell growth. As an m6A "writer", WTAP increased the m6A level of PD1 mRNA, thereby promoting YTHDF1-mediated translation of PD1. Finally, in the HuNSG xenograft tumor model, WTAP knockdown not only alleviated CD8+ T cell exhaustion and inhibited tumor progression but also synergistically enhanced the antitumor efficacy of anti-PD1 therapy. In conclusion, WTAP promoted CD8+ T cell exhaustion and HCC progression by facilitating the m6A modification and translation of PD1 mRNA.
    Keywords:  N6-methyladenosine; PD1; T cell exhaustion; WTAP; liver cancer
    DOI:  https://doi.org/10.1155/mi/6217272
  19. J Control Release. 2025 Jun 21. pii: S0168-3659(25)00598-X. [Epub ahead of print]385 113977
    Nucleic acid-based nanogels with "offensive and defensive"effects for enhanced chemo-immunotherapy.
    Zijian Zhao, Fei Sun, Wenyu Wang, Bing Li, Yan Liang, Dengshuai Wei, Yong Sun, Jianqin Yan.
      Chemotherapeutic drugs such as doxorubicin (DOX) can activate CD8+ T cell-mediated antitumor immune responses by inducing immunogenic cell death (ICD), demonstrating the potential of chemo-immune synergistic therapy. However, the continuous stimulation of tumor antigens triggers the exhaustion of CD8+ T cells, which has become the main obstacle to inhibiting tumor growth and metastasis. Dual regulation of T cell infiltration and exhaustion to elicit a robust immune response is the key for optimizing tumor immunotherapy. In this study, a membrane-coated framework nucleic acid-based nanogel (RM@NG/DOX) was developed to co-deliver DOX and siRNA (siTOX, thymocyte selection-associated high mobility group box protein, TOX) for the spatiotemporal synergistic regulation of chemo-immunotherapy. This system broke the traditional cationic carrier mode of siRNA delivery and constructed a double-layer barrier to further protect the loaded siTOX and DOX. RM@NG/DOX induced ICD by DOX as an "offensive" signal to enhance T cell infiltration, while siTOX as a "defensive module" reversed the differentiation of exhausted T cells (PD-1+ Tim-3+) by silencing TOX, a key regulator of T cell exhaustion. Experiments in vitro and in vivo confirmed that RM@NG/DOX reshaped the immune microenvironment through the dual pathway of "activation-reversal" to effectively inhibit tumor growth and metastasis, successfully transforming the "cold tumor" into an immune-infiltrated "hot tumor" and enhancing chemo-immunotherapy. In summary, the combined chemo-genetic nanomedicine based on nucleic acid nanogels provides a new strategy for chemo-immunotherapy and the regulation of T cell exhaustion.
    Keywords:  Chemo-immunotherapy; Immunogenic cell death; Nucleic acid Nanogels; T cell exhaustion; siRNA
    DOI:  https://doi.org/10.1016/j.jconrel.2025.113977
  20. Front Immunol. 2025 ;16 1622928
    Regulation of actin cytoskeletal dynamics in T cell development and function.
    Trang T Lam, Mark M W Chong.
      T cell development and function depend on precise remodeling of the actin cytoskeleton, which regulates migration, cell division, immunological synapse formation, and signal transduction. Regulators of actin include nucleators (Arp2/3, Formins) and binding proteins (coronins, cofilin, myosin) that orchestrate cytoskeletal dynamics to ensure efficient antigen recognition and signaling, while Rho GTPases (Rac1, Cdc42, RhoA) link extracellular cues to actin rearrangements, influencing both conventional T cell activation and function. Dysregulated actin dynamics contribute to immunodeficiencies and autoimmunity, and thus understanding how the actin cytoskeleton is regulated in T cells has important implications.
    Keywords:  T cell development; T cells; actin cytoskeletal dynamics; actin-binding proteins; coronin; immunological synapse
    DOI:  https://doi.org/10.3389/fimmu.2025.1622928
  21. Nat Immunol. 2025 Jun 25.
    Beneficial role of GZMK+CD8+ T cells in neurodegeneration.
      
    DOI:  https://doi.org/10.1038/s41590-025-02209-4
  22. Cell Stem Cell. 2025 Jun 17. pii: S1934-5909(25)00226-7. [Epub ahead of print]
    Hallmarks of stem cell aging.
    Thomas A Rando, Anne Brunet, Margaret A Goodell.
      As organisms age, somatic stem cells progressively lose their ability to sustain tissue homeostasis and support regeneration. Although stem cells are relatively shielded from some cellular aging mechanisms compared with their differentiated progeny, they remain vulnerable to both intrinsic and extrinsic stressors. In this review, we delineate five cardinal features that characterize aged stem cells and examine how these alterations underlie functional decline across well-studied stem cell compartments. These hallmarks not only provide insight into the aging process but also serve as promising targets for therapeutic strategies aimed at rejuvenating stem cell function and extending tissue health span.
    Keywords:  aging; differentiation; hematopoietic stem cells; heterogeneity; muscle stem cells; neural stem cells; quiescence; stem cells
    DOI:  https://doi.org/10.1016/j.stem.2025.06.004
  23. Immun Ageing. 2025 Jun 21. 22(1): 25
    The aging immune system and all-cause mortality in older americans: differences across sex and race/ethnicity.
    Kate A Duchowny, Yuan S Zhang, Rebecca C Stebbins, Xin Ma, Jaydon Jun Yu Chin, Virginia W Chang, Allison E Aiello, Grace A Noppert.
       BACKGROUND: As individuals age, the immune system undergoes complex changes, including an increase in the number of CD8 T cells relative to CD4 T cells, a decline in naïve cell production (including T and B cells), and an accumulation of terminally differentiated cells with diminished functionality. These age-related immune alterations collectively contribute to immunosenescence, a phenotype associated with aging-related declines and diseases such as dementia, Alzheimer's disease, osteoporosis, and diabetes. Premature mortality at older ages often results from cumulative health deterioration initiated by physiological dysregulation over the life course. Mortality risk, therefore, provides a meaningful measure of the long-term impact of physiological changes, including those related to the immune system. Examining the link between mortality risk and immune aging in older adults could illuminate the underlying pathology of aging-related health decline. This study uses data from the Health and Retirement Study (HRS), a national, population-based sample of middle-aged and older Americans, to explore the relationship between specific immune aging ratios and six-year mortality, stratified by race/ethnicity and sex.
    RESULTS: Using a sample of 8,259 individuals from the HRS, we found that overall, the presence, magnitude, and direction of the association differed by the specific immune ratio measure, sex, and race/ethnicity. We found particularly robust associations among Hispanic and non-Hispanic Black females. Among Hispanic females, for example, a one-unit increase in the log CD4 EMRA: Naïve ratio was associated with a nearly 50% increase in mortality for Hispanic females and a 25% increase in mortality for non-Hispanic Black females which was robust to adjustment for additional covariates. While we found little evidence of an association between immune function and mortality among non-Hispanic White and Hispanic males, we found associations in the opposite direction as what we would expect among non-Hispanic Black males. For example, a one-unit increase in the CD4, EMRA: Naïve ratio was associated with a 15% decrease in mortality among non-Hispanic Black males.
    CONCLUSIONS: Our findings demonstrate that associations between immune aging and mortality are not uniform but instead vary in magnitude and direction across sex and racial/ethnic subgroups. The strongest and most consistent associations were observed among Hispanic and non-Hispanic Black females-groups experiencing multiple forms of marginalization-suggesting that these populations may face heightened vulnerability to the downstream consequences of immune aging. However, the absence or reversal of expected associations in some subgroups-particularly non-Hispanic Black males-underscores the complexity of immune aging processes and their interaction with social and biological contexts. These results highlight the importance of disaggregated analyses and suggest that immune aging may manifest and impact mortality risk differently across populations.
    Keywords:  Disparities; Immunosenescence; Mortality; Population health; Social determinants
    DOI:  https://doi.org/10.1186/s12979-025-00521-z
  24. Oncoimmunology. 2025 Dec;14(1): 2521391
    Human cDC1 enhance cytotoxic function of CD226+ terminally exhausted tumor-infiltrating lymphocytes.
    Liam O'Brien, Irina Buckle, Ingrid M Leal-Rojas, Nikita Rosendahl, Kristen J Radford.
      Prevention or reversal of T cell exhaustion is a major objective of cancer immunotherapy. However, few models exist to generate, characterize and modulate exhausted human T cells, particularly within solid tumors in vivo, which likely hampers the discovery and translation of novel therapeutics. In this study we describe a humanized mouse model where functional human CD8+ T cells specific for the tumor antigen NY-ESO-1 develop in vivo from human CD34+ hematopoietic stem cells genetically modified to express a HLA-A *0201-restricted NY-ESO-1 specific T cell receptor (TCR). HLA-A *0201+ NY-ESO-1+ expressing A375 melanoma tumors engrafted in these mice and were refractory to treatment with anti-PD-1 despite being infiltrated with NY-ESO-1 specific T cells. Tumor-Infiltrating Lymphocytes (TIL) upregulated tissue resident memory (TRM) markers CD103 and CD69 along with exhaustion markers PD-1, TIGIT, and CD39 relative to T cells from other organs. Further, TILs failed to secrete cytokines TNF and IFNγ following in vitro stimulation with conventional Type I Dendritic Cells (cDC1), indicative of terminal exhaustion. However, cDC1 stimulation of the terminally exhausted NY-ESO-1 specific TILs led to enhanced tumor killing that was associated with increased CD107a and Granzyme B expression that was restricted to a subset of CD226+ NY-ESO-1 specific TILs. These findings establish a novel platform to investigate T cell exhaustion in human tumors and suggest a role for cDC1 in enhancing terminally exhausted TIL cytotoxic function.
    Keywords:  CD226; Humanized mice; T cell exhaustion; cDC1 dendritic cells; melanoma
    DOI:  https://doi.org/10.1080/2162402X.2025.2521391
  25. Aging Cell. 2025 Jun 25. e70147
    CD38-Targeting Peptide Vaccine Ameliorates Aging-Associated Phenotypes in Mice.
    Shangcheng Yu, Zhiqiang Li, Yuxiang Tang, Yuling Chen, Yingying Ma, Kunlin Du, Zhaoyun Zong, Kangze Feng, Yali Wei, Limeng Chen, Haiteng Deng.
      Antiaging vaccines have recently been found to elicit long-term benefits in slowing the aging process. Meanwhile, high CD38 expression in organs is an aging characteristic contributing to a decreased NAD+/NADH ratio. Thus, in the current study, we systematically investigate the effects of a CD38-targeting peptide vaccine (CD38-vaccine) on aging-associated phenotypes in mice. The CD38-vaccine induces a robust T-cell immune response, selectively depletes CD38+ myeloid cells in the spleen, and ameliorates age-related physical and cognitive function decline. Metabolically, vaccination improves glucose tolerance, enhances oxygen consumption, and decreases the number of senescent cells and mRNA levels of senescence-related genes in liver tissues. Vaccination also increases the NAD+/NADH ratio in the liver tissues, enhances oxidative metabolism, and reduces glycolysis. These findings indicate that targeting CD38 via vaccination is a promising strategy for ameliorating aging-associated phenotypes.
    Keywords:  CD38; aging; peptide; vaccine
    DOI:  https://doi.org/10.1111/acel.70147
  26. J Control Release. 2025 Jun 20. pii: S0168-3659(25)00596-6. [Epub ahead of print] 113975
    Mitochondria-targeted NAD+/O2 co-delivery interpenetrating network hydrogel for respiratory chain restoration and osteoarthritis therapy.
    Xiaolong Shen, Jinquan Hu, Chen Wang, Haoyi Wang, Huajian Zhong, Zifan Zhang, Guoqing Wen, Lei Wang, Minjie Dong, Ye Tian.
      Mitochondrial respiratory chain dysfunction-induced chondrocyte senescence is a key contributor to the progression of osteoarthritis (OA), yet effective strategies for restoring mitochondrial respiratory homeostasis remain elusive. Herein, we develop a charge-guided micro/nano interpenetrating network hydrogel that targets cartilage and delivers a mitochondria-directed MnO2-based nanoparticles, in which the nanozyme catalyzes intracellular hydrogen peroxide to generate oxygen while releasing nicotinamide adenine dinucleotide (NAD+) precursor via particle degradation, thereby enabling synchronized electron donor and acceptor supply to fully reactivate the mitochondrial respiratory chain and alleviate chondrocyte senescence. Comprehensive evaluations reveal that this system enhances the activity of key antioxidant enzymes including superoxide dismutase, catalase, and glutathione peroxidase, elevates the intracellular nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide hydrogen (NAD+/NADH) ratio, and suppresses the secretion of senescence-associated secretory phenotype factors, thereby preserving cartilage matrix integrity. Collectively, these findings underscore the therapeutic potential of this dual-delivery platform to achieve full-length mitochondrial respiratory chain activation, offering a compelling strategy to mitigate chondrocyte senescence and impede OA progression.
    Keywords:  Cartilage repair; Cellular senescence; Hydrogel; NAD(+); Osteoarthritis
    DOI:  https://doi.org/10.1016/j.jconrel.2025.113975
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