bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–04–06
nineteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Metabolic reprogram and T cell differentiation in inflammation: current evidence and future perspectives.
  2. Tumor-derived extracellular vesicles: Hijacking T cell function through exhaustion.
  3. Single cell-resolved cellular, transcriptional, and epigenetic changes in mouse T cell populations linked to age-associated immune decline.
  4. Harnessing Immune Rejuvenation: Advances in Overcoming T Cell Senescence and Exhaustion in Cancer Immunotherapy.
  5. Targeting CD36 to reinvigorate CD8+ T Cells in early-stage hepatocellular carcinoma.
  6. Developmental epigenetic programming by Tet1/3 determines peripheral CD8 T cell fate.
  7. 4-1BB stimulation with concomitant inactivation of adenosine A2B receptors enhances CD8+ T cell antitumor response.
  8. Impact of rosuvastatin on the memory potential and functionality of CD8+ T cells from people with HIV.
  9. Sodium citrate pretreatment enhances CAR-T cell persistence and anti-tumor efficacy through inhibition of calcium signaling.
  10. GSK-3 regulates CD4-CD8 cooperation needed to generate super-armed CD8+ cytolytic T cells against tumors.
  11. ABHD11 inhibition drives sterol metabolism to modulate T cell effector function and alleviate autoimmunity.
  12. Hexokinase2-engineered T cells display increased anti-tumor function.
  13. Single cell multi-omics reveals re-dosing with CD3 bispecific antibody induces a TCF7 high central memory CD8 + T cell population associated with reduced cytokine production.
  14. Cancer-cell-derived cGAMP limits the activity of tumor-associated CD8+ T cells.
  15. DNA-PKcs governs LAT-dependent signaling in CD4 + and CD8 + T cells.
  16. Humanizing a CD28 signaling domain affects CD8 activation, exhaustion and stem-like precursors.
  17. Iron and energy metabolic interactions in Treg-mediated immune regulation.
  18. Direct delivery of immune modulators to tumour-infiltrating lymphocytes using engineered extracellular vesicles.
  19. KLF2 inhibition expands tumor-resident T cells and enhances tumor immunity.
  1. Cell Death Discov. 2025 Mar 28. 11(1): 123
    Metabolic reprogram and T cell differentiation in inflammation: current evidence and future perspectives.
    Yuxin Shi, Hao Zhang, Changhong Miao.
      T cell metabolism and differentiation significantly shape the initiation, progression, and resolution of inflammatory responses. Upon activation, T cells undergo extensive metabolic shifts to meet distinct functional demands across various inflammatory stages. These metabolic alterations are not only critical for defining different T cell subsets, but also for sustaining their activity in inflammatory environments. Key signaling pathways-including mTOR, HIF-1α, and AMPK regulate these metabolic adaptions, linking cellular energy states with T cell fate decisions. Insights into the metabolic regulation of T cells offer potential therapeutic strategies to manipulate T cell function, with implications for treating autoimmune diseases, chronic inflammation, and cancer by targeting specific metabolic pathways.
    DOI:  https://doi.org/10.1038/s41420-025-02403-1
  2. Pathol Res Pract. 2025 Mar 29. pii: S0344-0338(25)00140-2. [Epub ahead of print]269 155948
    Tumor-derived extracellular vesicles: Hijacking T cell function through exhaustion.
    RuiJuan Guo, Ping Wang.
      Extracellular vesicles (EVs) play a vital role in intercellular communication within the tumor microenvironment (TME). These vesicles, secreted by tumor cells, contain proteins, lipids, and nucleic acids that significantly influence immune responses, particularly impacting T-cell function. In cancer, T cell dysfunction and exhaustion-marked by reduced proliferation, diminished cytokine production, and impaired cytotoxic activity-are key barriers to effective immune responses. Tumor-derived extracellular vesicles (TEVs) contribute to this dysfunction by carrying immunosuppressive molecules, such as transforming growth factor-beta (TGF-β) and various microRNAs (miRNAs). These TEV-mediated mechanisms promote T cell exhaustion and foster a broader immunosuppressive environment, enabling tumor progression and immune evasion. Furthermore, TEVs have been implicated in resistance to cancer immunotherapies, including immune checkpoint inhibitors and T cell therapies. Understanding the molecular pathways and cargoes within TEVs that drive T cell dysfunction is crucial for developing novel therapeutic strategies aimed at reinvigorating exhausted T cells, enhancing anti-tumor immunity, and improving cancer treatment outcomes.
    Keywords:  Exhaustion; Extracellular vesicles; T cell; Tumor-derived extracellular vesicles
    DOI:  https://doi.org/10.1016/j.prp.2025.155948
  3. Proc Natl Acad Sci U S A. 2025 Apr 08. 122(14): e2425992122
    Single cell-resolved cellular, transcriptional, and epigenetic changes in mouse T cell populations linked to age-associated immune decline.
    Jing He, Elena Burova, Chandrika Taduriyasas, Min Ni, Christina Adler, Yi Wei, Nicole Negron, Kun Xiong, Yu Bai, Tea Shavlakadze, Ella Ioffe, John C Lin, Adolfo Ferrando, David J Glass.
      Splenic T cells are pivotal to the immune system, yet their function deteriorates with age. To elucidate the specific aspects of T cell biology affected by aging, we conducted a comprehensive multi-time point single-cell RNA sequencing study, complemented by single-cell Assay for Transposase Accessible Chromatin (ATAC) sequencing and single-cell T cell repertoire (TCR) sequencing on splenic T cells from mice across 10 different age groups. This map of age-related changes in the distribution of T cell lineages and functional states reveals broad changes in T cell function and composition, including a prominent enrichment of Gzmk+ T cells in aged mice, encompassing both CD4+ and CD8+ T cell subsets. Notably, there is a marked decrease in TCR diversity across specific T cell populations in aged mice. We identified key pathways that may underlie the perturbation of T cell functions with aging, supporting cytotoxic T cell clonal expansion with age. This study provides insights into the aging process of splenic T cells and also highlights potential targets for therapeutic intervention to enhance immune function in the elderly. The dataset should serve as a resource for further research into age-related immune dysfunction and for identifying potential therapeutic strategies.
    Keywords:  T cells; aging; aging gene signature; granzyme K; single-cell RNA
    DOI:  https://doi.org/10.1073/pnas.2425992122
  4. Aging Cell. 2025 Apr 03. e70055
    Harnessing Immune Rejuvenation: Advances in Overcoming T Cell Senescence and Exhaustion in Cancer Immunotherapy.
    Tesfahun Dessale Admasu, John S Yu.
      Immunotherapy has transformed the landscape of cancer treatment, with T cell-based strategies at the forefront of this revolution. However, the durability of these responses is frequently undermined by two intertwined phenomena: T cell exhaustion and senescence. While exhaustion is driven by chronic antigen exposure in the immunosuppressive tumor microenvironment, leading to a reversible state of diminished functionality, senescence reflects a more permanent, age- or stress-induced arrest in cellular proliferation and effector capacity. Together, these processes represent formidable barriers to sustained anti-tumor immunity. In this review, we dissect the molecular underpinnings of T cell exhaustion and senescence, revealing how these dysfunctions synergistically contribute to immune evasion and resistance across a range of solid tumors. We explore cutting-edge therapeutic approaches aimed at rewiring the exhausted and senescent T cell phenotypes. These include advances in immune checkpoint blockade, the engineering of "armored" CAR-T cells, senolytic therapies that selectively eliminate senescent cells, and novel interventions that reinvigorate the immune system's capacity for tumor eradication. By spotlighting emerging strategies that target both exhaustion and senescence, we provide a forward-looking perspective on the potential to harness immune rejuvenation. This comprehensive review outlines the next frontier in cancer immunotherapy: unlocking durable responses by overcoming the immune system's intrinsic aging and exhaustion, ultimately paving the way for transformative therapeutic breakthroughs.
    Keywords:  CAR‐T; T cell exhaustion; T cell senescence; immune checkpoints; immune rejuvenation; immunosenescence; immunotherapy; senolytic therapy; solid tumors
    DOI:  https://doi.org/10.1111/acel.70055
  5. Clin Mol Hepatol. 2025 Mar 31.
    Targeting CD36 to reinvigorate CD8+ T Cells in early-stage hepatocellular carcinoma.
    Valerie Chew.
      
    Keywords:  CD36; CD8 T cell; HCC; NRF2; T cell exhaustion; tumour microenvironment
    DOI:  https://doi.org/10.3350/cmh.2025.0334
  6. EMBO Rep. 2025 Apr 02.
    Developmental epigenetic programming by Tet1/3 determines peripheral CD8 T cell fate.
    Kara M Misel-Wuchter, Andrew L Thurman, Jordan T Johnson, Athmane Teghanemt, Neelam Gautam, Alejandro A Pezzulo, Jennifer R Bermick, Noah S Butler, Priya D Issuree.
      In response to infections, naive CD8 T cells give rise to effector and memory T cells. However, eliciting long-lived memory CD8 T cells remains a challenge for many infections. DNA demethylation of cytosines within CpG dinucleotides by Tet enzymes is a key epigenetic mechanism that regulates short- and long-term transcriptional programs in cells. Currently, their roles in modulating CD8 T-cell effector and memory differentiation are unclear. Here, we report that developing CD8 T cells lacking Tet1/3 preferentially differentiate into short-lived effector and effector memory cells following acute infection. Using genome-wide analyses, mice in which Tet1/3 were ablated during T-cell development and mature CD8 T cells, respectively, we show that Tet1/3 regulates these cell fates by licensing the chromatin landscape of genes downstream of T-cell receptor activation during thymic T-cell maturation. However, in mature CD8 T cells, Tet1/3 are dispensable for effector and memory cell fates. These findings unveil context-specific roles of DNA demethylation, which are essential for defining pathways that contribute to CD8 memory T-cell generation in response to infections.
    Keywords:  DNA Demethylation; Effector CD8 T Cells; Epigenetics; Memory CD8 T Cells; T-Cell Development
    DOI:  https://doi.org/10.1038/s44319-025-00439-z
  7. J Clin Invest. 2025 Apr 03. pii: e190841. [Epub ahead of print]
    4-1BB stimulation with concomitant inactivation of adenosine A2B receptors enhances CD8+ T cell antitumor response.
    Jihae Ahn, Ping Xie, Siqi Chen, Guilan Shi, Jie Fan, Minghui Zhang, Hui Tang, Amanda R Zuckerman, Deyu Fang, Yong Wan, Timothy M Kuzel, Yi Zhang, Bin Zhang.
      Activating the immune co-stimulatory receptor 4-1BB (CD137) with agonist antibody binding and crosslinking-inducing agents that elicit 4-1BB intracellular signaling potentiates the antitumor responses of CD8 T cells. However, the underlying in-depth mechanisms remain to be defined. Here, we show that agonistic 4-1BB treatment of activated CD8+ T cells under continuous antigenic stimulation are more metabolically vulnerable to redox perturbation by ablation of intracellular glutathione (GSH) and glutathione peroxidase 4 (GPX4) inhibition. Further, genetic deletion of adenosine A2B receptor (A2BR) induces superior survival and expansion advantage of competent CD8+ T cells with agonistic 4-1BB costimulation, leading to more effective antitumor efficacy of adoptive cell therapy (ACT). Mechanistically, A2BR deletion helps sustain the increased energy and biosynthetic requirements through the GSH-GPX4 axis upon 4-1BB costimulation. A2BR deletion in combination with agonistic 4-1BB costimulation displays a greater ability to promote antitumor CD8+ effector T cell survival and expansion while mitigating T cell exhaustion. Thus, the A2BR pathway plays an important role in metabolic reprogramming with potentiation of the GSH-GPX4 cascade upon agonistic 4-1BB costimulation that allows the fine-tuning of the antitumor responses of CD8+ T cells.
    Keywords:  Adaptive immunity; Immunology; Immunotherapy; Oncology; T cells
    DOI:  https://doi.org/10.1172/JCI190841
  8. EBioMedicine. 2025 Mar 29. pii: S2352-3964(25)00116-1. [Epub ahead of print]114 105672
    Impact of rosuvastatin on the memory potential and functionality of CD8+ T cells from people with HIV.
    Federico Perdomo-Celis, Caroline Passaes, Valérie Monceaux, Olivier Lambotte, Dominique Costagliola, Mathieu F Chevalier, Laurence Weiss, Asier Sáez-Cirión.
       BACKGROUND: Virus-specific CD8+ T cells play a major role in the natural control of HIV infection, linked to memory-like features such as high survival capacity and polyfunctionality. However, virus-specific CD8+ T cells from HIV non-controllers exhibit an effector-like and exhausted profile, with limited antiviral potential. Metabolic reprogramming of cells from non-controllers could reinvigorate their functional capacities. Considering the implication of the cholesterol pathway in the induction of T cell exhaustion, here we evaluated the impact of rosuvastatin, an inhibitor of cholesterol synthesis, on the functionality and memory profile of HIV-specific CD8+ T cells from people on antiretroviral treatment.
    METHODS: We analysed samples from 10 individuals with HIV-1 on ART who participated in the IMEA 043-CESAR trial and received rosuvastatin for 12 weeks. We explored whether rosuvastatin treatment was accompanied by changes in the memory potential of CD8+ T cells. We evaluated the phenotype and functionality of total and HIV-specific CD8+ T cells before, during, and after treatment with rosuvastatin. A mixed effects model was used for repeated measures and corrected for multiple comparisons.
    FINDINGS: Total and HIV-specific CD8+ T cell survival and functionality were enhanced in individuals who received a 12-week course of rosuvastatin, with a consistent increase in polyfunctional IFN-γ+ TNF-α+ cells. The superior CD8+ T cell functionality after rosuvastatin treatment was associated with intrinsic metabolic changes, including the decrease of fatty acid uptake, as well as a reduction in effector/exhaustion markers. Changes in the characteristics of CD8+ T cells coincided with the duration of rosuvastatin administration, and most effects waned after the cessation of the treatment.
    INTERPRETATION: CD8+ T cell metabolic reprogramming by targeting the cholesterol pathway, combined with other available immunotherapies, might represent a promising strategy in the search for the cure of HIV or other chronic viral infections.
    FUNDING: The CESAR trial was sponsored by IMEA. This work was supported by the NIH (grants UM1AI164562 and R01DK131476).
    Keywords:  CD8(+) T cells; HIV control; HIV remission; HIV-1; Statins; T cell reprogramming
    DOI:  https://doi.org/10.1016/j.ebiom.2025.105672
  9. Front Immunol. 2025 ;16 1540754
    Sodium citrate pretreatment enhances CAR-T cell persistence and anti-tumor efficacy through inhibition of calcium signaling.
    Xuechen Yin, Wenwen Chen, Xudong Ao, Luxia Xu, Jiujiu Cao, Tinghui Huang, Junqing Liang, Jianhua Hu, Jiaqi Liu, Xinping Wang, Wenying Li, Muya Zhou, Lingfeng He, Zhigang Guo.
       Introduction: Chimeric antigen receptor T cell (CAR-T) therapy has shown success in treating hematological malignancies, but its effectiveness against solid tumors is hindered by T cell exhaustion. During in vitro expansion, tonic signaling induced by CAR expression contributes to CAR-T cell exhaustion, which can be mitigated by inhibiting calcium signaling. Given that sodium citrate can chelate calcium ions and inhibit calcium signaling, in this study, we investigated whether sodium citrate could reduce exhaustion and enhance CAR-T cell function.
    Methods: We constructed anti-CD70 CAR-T cells and cultured them in the presence of sodium citrate. The characteristics and functionality of sodium citrate-pretreated CAR-T cells were assessed through in vitro and in vivo experiments. To further validate our observation, we also treated anti-mesothelin (MSLN) CAR-T cells with sodium citrate and detected the phenotypes and anti-tumor function of CAR-T cells.
    Results: We found that sodium citrate-pretreated anti-CD70 CAR-T cells exhibited reduced exhaustion, increased memory T cell proportions, and enhanced anti-tumor efficacy both in vitro and in vivo. Notably, sodium citrate treatment improved the in vivo persistence of CAR-T cells and prevented tumor recurrence. These beneficial effects were also observed in anti-MSLN CAR-T cells. Transcriptomic and metabolite analyses revealed that sodium citrate inhibited calcium signaling, mTORC1 activity, and glycolysis pathways, thus modulating T cell exhaustion and differentiation.
    Discussion: Our findings suggest that sodium citrate supplementation during CAR-T cell expansion could be a promising strategy to improve CAR-T therapy for solid tumors by preventing exhaustion and promoting memory T cell formation.
    Keywords:  CAR-T; T cell exhaustion; calcium ions; cancer immunotherapy; sodium citrate; solid tumors
    DOI:  https://doi.org/10.3389/fimmu.2025.1540754
  10. bioRxiv. 2025 Mar 12. pii: 2025.03.08.642085. [Epub ahead of print]
    GSK-3 regulates CD4-CD8 cooperation needed to generate super-armed CD8+ cytolytic T cells against tumors.
    Bastien Moës, Janna Krueger, Alexandra Kazanova, Chen Liu, Yunfeng Gao, Nikhil Anto Ponnoor, Linda Castoun-Puckett, Andres Carlos Oroya Lazo, Lan Huong, Auryane Laure Cabald, Thai Hien Tu, Christopher E Rudd.
      While immune checkpoint inhibitor therapy has transformed cancer treatment, the signaling pathways underlying T-cell function optimization remain incompletely understood. While glycogen synthase kinase-3 (GSK-3) is a negative regulator and CD4+ T-cells provide help for CD8+ T-cell development, the signaling events controlling CD4-CD8 T-cell cooperation are unclear. Here, using GSK-3 knock-down mice (GSK-3KD), we show that GSK-3 is the central regulator of CD4-CD8 cooperation, specifically in enhancing the expression of granzymes necessary for CD8+ CTL killing. GSK-3KD induced metabolic reprogramming toward glycolysis in T-cells and, when combined with PD-1 blockade, overcame tumor checkpoint resistance characterized by reduced Treg TILs and increased effector-memory CD8+ TILs. GSK-3KD with anti-PD-1 therapy induced unprecedented expression of seven out of nine granzymes in CD8+ TILs through enhanced CD4+ T-cell help. These findings identify GSK-3 as a key regulator of CD4+ T-cell help in generating highly cytotoxic CD8+ T-cells, presenting a promising therapeutic strategy for cancer treatment.
    DOI:  https://doi.org/10.1101/2025.03.08.642085
  11. bioRxiv. 2025 Mar 19. pii: 2025.03.19.643996. [Epub ahead of print]
    ABHD11 inhibition drives sterol metabolism to modulate T cell effector function and alleviate autoimmunity.
    Benjamin J Jenkins, Yasmin R Jenkins, Fernando M Ponce-Garcia, Chloe Moscrop, Iain A Perry, Matthew D Hitchings, Alejandro H Uribe, Federico Bernuzzi, Simon Eastham, James G Cronin, Ardena Berisha, Alexandra Howell, Joanne Davies, Julianna Blagih, Douglas J Veale, Luke C Davies, Micah Niphakis, David K Finlay, Linda V Sinclair, Benjamin F Cravatt, Andrew E Hogan, James A Nathan, Ursula Fearon, David Sumpton, Johan Vande Voorde, Goncalo Dias do Vale, Jeffrey G McDonald, Gareth W Jones, James A Pearson, Emma E Vincent, Nicholas Jones.
      Chronic inflammation in autoimmunity is driven by T cell hyperactivation. This unregulated response to self is fuelled by heightened metabolic programmes, which offers a promising new direction to uncover novel treatment strategies. α/β-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase that maintains the catalytic function of α-ketoglutarate dehydrogenase (α-KGDH), and its expression in CD4+ T cells has been linked to remission status in rheumatoid arthritis (RA). However, the importance of ABHD11 in regulating T cell metabolism and function - and thus, the downstream implication for autoimmunity - is yet to be explored. Here, we show that pharmacological inhibition of ABHD11 dampens cytokine production by human and mouse T cells. Mechanistically, the anti-inflammatory effects of ABHD11 inhibition are attributed to increased 24,25-epoxycholesterol (24,25-EC) biosynthesis and subsequent liver X receptor (LXR) activation, which arise from a compromised TCA cycle. The impaired cytokine profile established by ABHD11 inhibition is extended to two patient cohorts of autoimmunity. Importantly, using a murine model of accelerated type 1 diabetes (T1D), we show that targeting ABHD11 suppresses cytokine production in antigen-specific T cells and delays the onset of diabetes in vivo . Collectively, our work provides pre-clinical evidence that ABHD11 is an encouraging drug target in T cell-mediated autoimmunity.
    DOI:  https://doi.org/10.1101/2025.03.19.643996
  12. Front Immunol. 2025 ;16 1477929
    Hexokinase2-engineered T cells display increased anti-tumor function.
    Raphaëlle Toledano Zur, Shiran Didi Zurinam, Maria Radman, Elia Funaro Balouka, Tatiana Borodianskiy-Shteinberg, Dieter Saur, Cyrille J Cohen.
       Background: T cells face significant metabolic challenges in the tumor microenvironment (TME), where cancer cells monopolize critical nutrients like glucose and amino acids. This metabolic competition supports tumor growth while impairing T-cell anti-tumor responses, partly by reducing glycolytic function. Hexokinase 2 (HK2), a key enzyme in glycolysis, plays a pivotal role in maintaining T-cell functionality.
    Methods: To enhance T-cell function, primary human T cells were genetically engineered to overexpress HK2 alongside a tumor-specific receptor. These engineered T cells were tested in vitro and in vivo to evaluate their metabolic and therapeutic efficacy.
    Results: HK2-engineered T cells exhibited increased glycolytic capacity, leading to enhanced cytokine secretion, activation marker expression, and metabolic activity compared to controls. In vivo studies using a human tumor xenograft model demonstrated the superior therapeutic efficacy of HK2-engineered T cells, including delayed tumor growth and improved survival.
    Conclusion: HK2 overexpression improves T-cell metabolic fitness and functionality in hostile TMEs, offering a promising foundation for the development of next-generation immunotherapies targeting T-cell metabolism.
    Keywords:  T-cells; TCR; cellular immunotherapy; hexokinase 2; immunometabolism
    DOI:  https://doi.org/10.3389/fimmu.2025.1477929
  13. Biomed Pharmacother. 2025 Mar 31. pii: S0753-3322(25)00167-2. [Epub ahead of print]186 117973
    Single cell multi-omics reveals re-dosing with CD3 bispecific antibody induces a TCF7 high central memory CD8 + T cell population associated with reduced cytokine production.
    Hui Ling, Lauren Anderson, Katie Kubek-Luck, Juliane Perner, Tyler Burks, Sven Schuierer, Vera M Ruda, Keith Mansfield.
       BACKGROUND: T cell engaging therapies are commonly accompanied by excessive cytokine production and risk of cytokine release syndrome (CRS). Intriguingly, CRS risk with CD3-engaging bispecific antibody (BSP) is primarily limited to the first dose, termed the first-dose effect. Mechanisms underlying this effect remain unknown. CD3 bispecific induces cytokine cascade via T cell triggering and bystander cells. We hypothesize that distinct T cell biology between doses drives the first-dose effect.
    METHODS: We used the Re-directed T Cell Cytotoxicity (RTCC) assay to assess tumor killing and cytokine production by human donor T cells after initial versus subsequent CD3/CD20 BSP treatment. After confirming the first-dose effect in the experimental system containing only T cells and target tumor cells, we employed 10x Genomics single cell multi-omics to study the molecular mechanisms.
    RESULTS: Compared with initial CD3/CD20 BSP treatment, subsequent treatment exhibited lower cytokine levels and comparable tumor killing. Single cell multi-omics unveiled distinct T cell biology. In initial treatment, T effector memory (Tem) cells are the primary cells that respond to CD3 bispecific antibody stimulus by producing moderate levels of cytolytic and high levels of cytokine gene transcription. In the subsequent treatment, a new population of high TCF7 expressing central memory CD8 + cells (CD8-Tcm-TCF7), possibly originated from stimulated naive T cells, are the primary responding cells that produce a shifted balance with high level of the cytolytic gene transcription (GZMB) and low level of cytokine gene transcription (TNF-alpha and IFN-gamma). Dasatinib co-treatment during initial treatment eliminated cytolytic activity and cytokine production, allowing uncompromised tumor killing and reduced cytokine production upon re-challenge.
    CONCLUSIONS: The distinct T cell populations that respond to first and subsequent CD3 bispecific treatment offer an explanation to the first-dose effect, wherein the risk of CRS associated with CD3 bispecific treatment is mainly limited to the initial dose. Furthermore, our work suggests that tumor killing capacity and cytokine production of T cells could be uncoupled, as demonstrated here by utilizing different T cell populations as effector cells. These findings could be further explored for designing mechanism-based strategies to mitigate the risk of CRS.
    Keywords:  CD3 bispecific; First-dose effect; Single cell multi-omics; TCF7
    DOI:  https://doi.org/10.1016/j.biopha.2025.117973
  14. Cell Rep. 2025 Apr 02. pii: S2211-1247(25)00281-5. [Epub ahead of print]44(4): 115510
    Cancer-cell-derived cGAMP limits the activity of tumor-associated CD8+ T cells.
    Michael Herbst, Hakan Köksal, Silvan Brunn, Dominik Zanetti, Ioana Domocos, Viola De Stefani, Marco Gatti, Francesca Vivalda, Paulo Pereira, Marc Nater, Virginia Cecconi, Alessandro A Sartori, Maries van den Broek.
      Using a mouse tumor model with inducible cancer-cell-intrinsic cyclic GMP-AMP (cGAMP) synthase (cGAS) expression, we show that cancer-cell-derived cGAMP is essential and sufficient to trigger a sustained type I interferon response within the tumor microenvironment. This leads to improved CD8+ T cell-dependent tumor restriction. However, cGAMP limits the proliferation, survival, and function of stimulator of IFN genes (STING)-expressing, but not of STING-deficient, CD8+ T cells. In vivo, STING deficiency in CD8+ T cells enhances tumor restriction. Consequently, cancer-cell-derived cGAMP both drives and limits the anti-tumor potential of CD8+ T cells. Mechanistically, T cell-intrinsic STING is associated with pro-apoptotic and antiproliferative gene signatures. Our findings suggest that STING signaling acts as a checkpoint in CD8+ T cells that balances tumor immunity.
    Keywords:  CD8(+); CP: Cancer; CP: Immunology; STING; T cells; cGAMP; cGAS; cancer; immunity; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2025.115510
  15. bioRxiv. 2025 Mar 10. pii: 2025.03.06.641745. [Epub ahead of print]
    DNA-PKcs governs LAT-dependent signaling in CD4 + and CD8 + T cells.
    Randall R Rainwater, Ana C Azevedo-Pouly, Zachary J Waldrip, Belle H Hicks, Nicholas A Callais, Brian Koss, Aaron J Storey, Lyle Burdine, Marie Schluterman Burdine.
      Formation of the immune synapse (IS) following T cell antigen recognition includes recruitment of the Linker for Activation of T cells (LAT). Once at the IS, LAT tyrosines are phosphorylated allowing it to serve as a scaffold for formation of the "signalosome", a multiprotein complex that drives TCR signaling. Here, we show that upon T cell activation, DNA dependent protein kinase catalytic subunit (DNA-PKcs) interacts with LAT and localizes to the IS. Inhibition of DNA-PKcs diminishes LAT localization at the IS. We identified two LAT serines phosphorylated by DNA-PKcs, S224 and S241, that impact LAT tyrosine phosphorylation, protein binding, and cytokine production. Using our mouse model designed to delete DNA-PKcs expression within mature CD4 + or CD8 + T cells, we show loss of DNA-PKcs results in T cells unable to control tumor growth or induce allogeneic graft rejection. These data bring to the forefront DNA-PKcs as a pivotal protein in T cell function.
    DOI:  https://doi.org/10.1101/2025.03.06.641745
  16. bioRxiv. 2025 Mar 13. pii: 2025.03.10.642460. [Epub ahead of print]
    Humanizing a CD28 signaling domain affects CD8 activation, exhaustion and stem-like precursors.
    Alexander E Brady, Shankar Revu, Dongwen Wu, Hannah Fisk, Khadija Kone, Alexandria Lydecker, Elliott J Purser, Norah Smith, Zachary T Hilt, Sarah Woodyear, Sarah Caddy, Sebastien Gingras, Brian Rudd, Mandy M McGeachy.
      CD28 ligation provides critical signals that modulate activated T cell fate. In a human to mouse reverse-engineering approach, a single amino acid substitution adjacent to the C-terminal proline-rich domain created CD28 A210P mice with enhanced signaling. CD28 A210P mice experienced pro-inflammatory responses to CD28 superagonist antibody, analogous to severe cytokine storm induced in a human clinical trial, with a striking increase of activated CD8 T cells. In acute and chronic viral infections, early activation and expansion of CD28 A210P CD8 effector T cells increased, with accelerated exhaustion in chronic infection. Mechanistically, CD28 A210P enhanced JunB, IL-2, and inhibitory receptors driven by MEK1/2. Generation of CD28 A210P stem-like progenitor (Tpex) cells was enhanced in acute and chronic infections, and further expanded by PD-L1 blockade in chronically-infected mice. Thus, 'humanized' PYAP mice reveal key roles for CD28 signaling strength in CD8 activation, accelerating exhaustion during antigen persistence, while promoting and sustaining Tpex during acute and chronic viral infection.
    One sentence Summary: A single amino acid substitution adjacent to PYAP to 'humanize' CD28 signaling enhances superagonist response, early CD8 activation and Tpex generation during viral infection while accelerating exhaustion and sustaining Tpex during chronic infection.
    DOI:  https://doi.org/10.1101/2025.03.10.642460
  17. Front Immunol. 2025 ;16 1554028
    Iron and energy metabolic interactions in Treg-mediated immune regulation.
    Frédérique Savagner, Thomas Farge, Zoubida Karim, Meryem Aloulou.
      Immunometabolism, the study of how metabolic processes influence immune cell function, has emerged as a critical field in understanding the regulation of immune tolerance and the pathological mechanisms underlying autoimmune diseases. Intracellular metabolic pathways not only provide the necessary energy for immune cell survival and activity but also shape the differentiation, phenotype, proliferation, and effector functions of immune cells. This is particularly evident in CD4+ Foxp3+ regulatory T cells (Treg), which are pivotal for maintaining immune homeostasis and preventing autoimmune reactions. Strong experimental evidence highlights the profound impact of metabolism on Treg. Their anti-inflammatory function and ability to suppress excessive immune responses depend on the integration of metabolic cues with their transcriptional and signaling networks. Iron metabolism and mitochondrial dynamics are among the key factors influencing Treg function. This review focuses on how iron and mitochondrial metabolism shape Treg biology and function.
    Keywords:  Foxp3; ROS; Treg; immunoregulation; iron; mitochondria
    DOI:  https://doi.org/10.3389/fimmu.2025.1554028
  18. J Extracell Vesicles. 2025 Apr;14(4): e70035
    Direct delivery of immune modulators to tumour-infiltrating lymphocytes using engineered extracellular vesicles.
    Xiabing Lyu, Tomoyoshi Yamano, Kanto Nagamori, Shota Imai, Toan Van Le, Dilireba Bolidong, Makie Ueda, Shota Warashina, Hidefumi Mukai, Seigo Hayashi, Kazutaka Matoba, Taito Nishino, Rikinari Hanayama.
      Extracellular vesicles (EVs) are important mediators of cell-cell communication, including immune regulation. Despite the recent development of several EV-based cancer immunotherapies, their clinical efficacy remains limited. Here, we created antigen-presenting EVs to express peptide-major histocompatibility complex (pMHC) class I, costimulatory molecule and IL-2. This enabled the selective delivery of multiple immune modulators to antigen-specific CD8+ T cells, promoting their expansion in vivo without severe adverse effects. Notably, antigen-presenting EVs accumulated in the tumour microenvironment, increasing IFN-γ+ CD8+ T cell and decreasing exhausted CD8+ T cell numbers, suggesting that antigen-presenting EVs transformed the 'cold' tumour microenvironment into a 'hot' one. Combination therapy with antigen-presenting EVs and anti-PD-1 demonstrated enhanced anticancer immunity against established tumours. We successfully engineered humanized antigen-presenting EVs, which selectively stimulated tumour antigen-specific CD8+ T cells. In conclusion, engineering EVs to co-express multiple immunomodulators represents a promising method for cancer immunotherapy.
    Keywords:  antigen presentation; cancer immunotherapy; drug delivery; extracellular vesicle; targeted cytokine delivery
    DOI:  https://doi.org/10.1002/jev2.70035
  19. Res Sq. 2025 Mar 13. pii: rs.3.rs-5966555. [Epub ahead of print]
    KLF2 inhibition expands tumor-resident T cells and enhances tumor immunity.
    Eli Gilboa, Vineet Gupta, Darija Muharemagic, Sunwoo Ham, Erietta Stelekati, Emily Clark.
      Tissue resident memory CD8+ T cells (Trm) constitute a distinct population of non-circulating memory T cells1-5 vastly exceeding the number of circulating T cells5, and play a pivotal role in protective immunity against pathogens6-8. How to promote the generation of vaccine specific Trm remains an important challenge. Whether Trm contribute also to immune control of tumors or just correlate with an unrelated process linked to clinical outcome has not been unequivocally established9,10, and phenotypic markers such as co-expression of CD69 and CD103 or CD49a integrins commonly used to monitor tumor infiltrating Trm do not unambiguously define this subset. Here we tested the hypothesis that transient downregulation of KLF2, the most conserved feature of Trm ontogeny4,11,12, will promote the differentiation of vaccine activated CD8+ T cells into Trm and enhance antitumor immunity. We show that 4-1BB antibody targeted delivery of a KLF2 siRNA to tumor bearing mice led to the downregulation of KLF2 in vaccine activated CD8+ T cells and the accumulation of phenotypically defined intratumoral CD69+CD103+ and CD69+CD49a+ CD8+ T cells which correlated with enhanced control of tumor growth. This study could serve as the foundation of a broadly applicable and clinically useful way to promote the generation of vaccine specific Trm and provides direct evidence that intratumoral CD8+CD69+CD103+ and CD8+CD69+CD49a+ cells are indeed Trm and that Trm contribute to tumor immunity.
    DOI:  https://doi.org/10.21203/rs.3.rs-5966555/v1
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