bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–10–12
29 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Proteotoxic shock is a mechanistic driver of T cell exhaustion.
  2. p38 signaling enhances short-lived effector cell differentiation and weakens central memory CD8+ T-cell formation.
  3. Autoimmune T cells identified in ALS.
  4. Faithful modeling of terminal CD8+T cell dysfunction and epigenetic stabilization in vitro.
  5. Targeting organelle function in T cells for cancer immunotherapy.
  6. Pre-Encoded IFN-I Sensitivity Exacerbates Memory T Cell Senescence in Solid Tumors.
  7. CD4 T cells acquire Eomesodermin to modulate cellular senescence and aging.
  8. The role of TCF-1+CD8+ exhausted progenitors and TCF-1 in graft-versus-host responses.
  9. Macrophage repolarization by immune checkpoint blockade drives T cell engagement in the tumor microenvironment.
  10. NK-Like CD8+ T Cells: Professional Assassins in Fulminant Myocarditis.
  11. DNAJA1 as a Modulator of CD8+ T-Cell Function and Prognosis in Lung Cancer: Implications for Immune Regulation and Therapeutic Targeting.
  12. Deciphering metabolic reprogramming of immune cells within the tumor microenvironment.
  13. Ferroptosis: A Novel Target to Rescue CD8+ T Cells Against Hepatitis B Virus.
  14. Comprehensive characterisation of age-related changes in cell subpopulations and tissue structural properties in secondary lymphoid organs.
  15. Mito-Specific "Trojan Horse" Nanotherapy: Synergistic Antitumor Immunotherapy via Dual Modulation Mitochondrial Metabolism and Glycolysis.
  16. Smarter combos, stronger T cells in lymphoma.
  17. Extracellular vesicles of patients with acute-on-chronic liver failure induce mitochondrial dysfunction in T cells.
  18. Molecular Mediators of Metabolic Reprogramming in Cancer: Mechanisms, Regulatory Networks, and Therapeutic Strategies.
  19. Microbial metabolites and their influence on the tumor microenvironment.
  20. Selective IL-2 delivery modulates CD8+ T cells in human HLH and ameliorates disease features in a murine model.
  21. CAR T cell therapy for meningioma: mesothelin emerges as a novel promising target.
  22. Age-Associated Expansion of HIV/SIV Reservoirs in People With HIV and SIV-Infected Macaques.
  23. T cell receptor associated transmembrane adaptor 1 (TRAT1) modulates human Th17 and Treg responses via PI3-kinase and STAT dependent mechanisms.
  24. Manufacturing synthetic viscoelastic antigen-presenting cells for immunotherapy.
  25. A Notch trans-activation to cis-inhibition switch underlies hematopoietic stem cell aging.
  26. Progenitor exhausted PD-1+ T cells are cellular targets of immune checkpoint inhibition in atherosclerosis.
  27. HRS sustains mitochondrial homeostasis by anchoring destabilized proteins during tumorigenesis.
  28. Metabolic profiling reveals channeled de novo pyrimidine and purine biosynthesis fueled by mitochondrially generated aspartic acid in cancer cells.
  29. Purin Metabolism Is Crucial for Regulatory T Cell Stability and Function.
  1. Nat Rev Immunol. 2025 Oct 07.
    Proteotoxic shock is a mechanistic driver of T cell exhaustion.
    Alexandra Flemming.
      
    DOI:  https://doi.org/10.1038/s41577-025-01236-4
  2. J Immunol. 2025 Oct 10. pii: vkaf214. [Epub ahead of print]
    p38 signaling enhances short-lived effector cell differentiation and weakens central memory CD8+ T-cell formation.
    Lichen Hu, Huaipeng Lin, Yubing Fu, Danying Li, Yu Cong, Wanyun Li, Zexu Wang, Lei Zhang, Guo Fu, Nengming Xiao, Jiahuai Han, Jianfeng Wu.
      Memory CD8+ T cells are essential for long-term protective immunity. Here, we show that activation of p38 MAPK during the primary response of CD8+ T cells orchestrates a delicate balance between the formation of short-lived effector cells and memory precursor effector cells. p38αfl/flp38βfl/flGzmBcre/- mice, in which p38α and p38β were efficiently deleted in CD8+ T cells and also in early stages of T-cell development, were used in studying the role of the p38 pathway in T cells. The deletion of p38α and p38β (simplified as p38α/β) has very minor effects on thymic and peripheral T-cell development. In contrast, p38α/β-deficient CD8+ T cells were skewed toward a central memory phenotype and mounted stronger recall responses upon secondary challenge. Transcriptomic analyses of antigen-specific CD8+ T cells revealed that p38α/β deficiency is associated with reduced effector gene expression and enhanced memory-associated programs. Furthermore, in vitro differentiated p38α/β-deficient CD8+ T cells showed superior persistence and functional responses after adoptive transfer. These results establish a role for p38 in controlling effector CD8+ T-cell differentiation and memory formation, and reinforce the therapeutic potential of targeting this pathway, aligning with recent studies demonstrating the beneficial effects of p38 inhibitors in adoptive cell therapy.
    Keywords:  CD8+ T cell; LCMV; cell differentiation; memory; p38
    DOI:  https://doi.org/10.1093/jimmun/vkaf214
  3. Nat Rev Immunol. 2025 Oct 08.
    Autoimmune T cells identified in ALS.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-025-01233-7
  4. JCI Insight. 2025 Oct 08. pii: e191220. [Epub ahead of print]10(19):
    Faithful modeling of terminal CD8+T cell dysfunction and epigenetic stabilization in vitro.
    Amir Yousif, Abbey A Saadey, Ava Lowin, Asmaa M Yousif, Ankita Saini, Madeline R Allison, Kelley Ptak, Eugene M Oltz, Hazem E Ghoneim.
      Epigenetic scarring of terminally dysfunctional (TDysf) CD8+ T cells hinders long-term protection and response to immune checkpoint blockade during chronic infections and cancer. We developed a faithful in vitro model for CD8+ T cell terminal dysfunction as a platform to advance T cell immunotherapy. Using TCR-transgenic CD8+ T cells, we found that 1-week peptide stimulation, mimicking conditions in previous models, failed to induce a stable exhaustion program. In contrast, prolonged stimulation for 2-3 weeks induced T cell dysfunction but triggered activation-induced cell death, precluding long-term investigation of exhaustion programs. To better mimic in vivo exhaustion, we provided post-effector, chronic TGF-β1 signals, enabling survival of chronically stimulated CD8+ T cells for over 3 weeks. These conditions induced a state of terminal dysfunction, marked by a stable loss of effector, cytotoxicity, and memory programs, along with mitochondrial stress and impaired protein translation. Importantly, transcriptomic and epigenetic analyses verified the development of terminal exhaustion-specific signatures in TDysf cells. Adoptive transfer of TDysf cells revealed their inability to recall effector functions or proliferate after acute lymphocytic choriomeningitis virus rechallenge. This tractable model system enables investigation of molecular pathways driving T cell terminal dysfunction and discovery of therapeutic targets for cancer or chronic infections.
    Keywords:  Adaptive immunity; Cancer immunotherapy; Epigenetics; Immunology; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.191220
  5. Nat Rev Immunol. 2025 Oct 09.
    Targeting organelle function in T cells for cancer immunotherapy.
    Jeremy G Baldwin, Christoph Heuser-Loy, Luca Gattinoni.
      Organelles are the internal batteries, gears, actuators, 3D printers and transmitters that drive cell function. Their composition and activity vary between cell types depending on functional demands. In T cells, which are key mediators of immunosurveillance and tumour eradication, organelles are relatively few and function at basal levels when cells are at rest. However, upon activation, they increase in number and size and undergo extensive remodelling to support rapid proliferation, effector differentiation and adaptation to diverse microenvironments, including the tumour microenvironment, thereby enabling efficient clearance of target cells. In this Review, we provide an overview of recent advances in our understanding of how various organelles contribute to T cell-mediated antitumour immunity. We also discuss emerging strategies to modulate organelle functions - from organelle-targeted therapies and their use as cargo delivery systems to the transfer or transplantation of native or synthetic organelles - that have the potential to enhance cancer immunotherapies involving immune-checkpoint blockade or the adoptive transfer of T cells.
    DOI:  https://doi.org/10.1038/s41577-025-01223-9
  6. Adv Sci (Weinh). 2025 Oct 05. e04474
    Pre-Encoded IFN-I Sensitivity Exacerbates Memory T Cell Senescence in Solid Tumors.
    Andrew Nguyen, Scott R Walsh, Li Deng, Lan Chen, Yonghong Wan.
      Solid tumors often suppress antitumor immune responses by promoting various dysfunctional CD8+ T cell states, which limit the effectiveness of T-cell-based immunotherapy. However, the mechanisms that promote these states have not been fully characterized. It is demonstrated that spontaneous priming responses during tumor growth can produce memory T cell reservoirs that are conducive to poor proliferative responsiveness during boosting vaccination. Surprisingly, when type I interferon (IFN-I) signaling is impeded, boosting vaccination can elicit robust proliferative responses from tumor-primed memory T cells and promote tumor control. This is observed in multiple tumor types and target antigens. In contrast to conventional memory T cells, tumor-primed memory T cells are unique in their pre-encoded responsiveness to IFN-I and show enrichment of pathways pertaining to DNA repair and cell cycle arrest. Tumor-primed memory T cells up-regulate p21 expression and blockade of either p21 or IFN-I can alleviate this effect to improve their proliferative capacity during boosting vaccination. Characterization of tumor-primed memory T cells revealed transcriptional and phenotypic features of cellular senescence, where higher senescence severity correlated with higher responsiveness to IFNα/β receptor blockade. Overall, IFN-I hyperresponsiveness may be a unique feature of senescent tumor-primed memory T cells that can exacerbate their dysfunction during cancer vaccination.
    Keywords:  T cell senescence; cancer immunotherapy; oncolytic virus; tumor microenvironment; type I interferon
    DOI:  https://doi.org/10.1002/advs.202504474
  7. Nat Aging. 2025 Oct 07.
    CD4 T cells acquire Eomesodermin to modulate cellular senescence and aging.
    Yehezqel Elyahu, Ilana Feygin, Ekaterina Eremenko, Noa Pinkas, Alon Zemer, Amit Shicht, Omer Berner, Roni Avigdory-Meiri, Anna Nemirovsky, Keren Reshef, Lior Roitman, Valery Krizhanovsky, Alon Monsonego.
      Aging is characterized by the progressive deterioration of tissue structure and function, leading to increased vulnerability to diseases. Senescent cells (SCs) accumulate with age, but how the immune system regulates their burden is unclear. Here we show that CD4 T cells differentiate into Eomesodermin (Eomes)+CCL5+ T lymphocytes (CD4-Eomes) in a SC-rich environment and that a reduction in the SC load, achieved using senolytic drugs, was sufficient to halt this differentiation. We further demonstrate that eliminating CD4-Eomes cells at advanced age by selectively deleting the Eomes transcription factor in CD4 T cells results in increased accumulation of SCs, profound physical deterioration and a decreased lifespan. In liver cirrhosis, a model of localized chronic inflammation, CD4-Eomes cell elimination increased fibrosis, SC load and worsened the disease. Collectively, our findings demonstrate the fundamental role of CD4-Eomes cells in modulating tissue senescence, with implications for age-related diseases and longevity.
    DOI:  https://doi.org/10.1038/s43587-025-00953-8
  8. JCI Insight. 2025 Oct 08. pii: e181568. [Epub ahead of print]10(19):
    The role of TCF-1+CD8+ exhausted progenitors and TCF-1 in graft-versus-host responses.
    Kevin Quann, Faruk Sacirbegovic, Sarah Rosenberger, Emily R McFerran, Kentin C Codispot, Laura Garcia-Dieguez, Alexander M Rowe, Wenzhong Wei, Dhanpat Jain, Jennifer M McNiff, Warren Shlomchik.
      In allogeneic hematopoietic transplantation, donor αβ T cells attack recipient tissues, causing graft versus host disease (GVHD). A longstanding question has been how GVHD is maintained despite T cell exhaustion from chronic alloantigen stimulation. In other exhaustion models, CD8 responses are sustained by CD39loTim-3loToxhiTCF-1hi precursor exhausted T cells (TPEX). Here we characterize CD8+ TPEX in the B6(H-2b)→129(H-2b) GVHD model wherein responses against the minor histocompatibility antigen H60 can be tracked using MHCI-tetramers (TetH60). Early after transplant, TetH60+ CD8 cells were uniformly PD-1hiToxhi, whereas TetH60- cells also had PD-1loToxlo cells, indicative of more diverse antigen experiences. Among TetH60+ and TetH60- populations were CD39loTCF-1hi cells. Upon competitive retransplantation, TetH60+CD39loTCF-1hi cells outcompeted TetH60+CD39hiTCF-1lo cells and underwent self-renewal, whereas CD39hiTCF-1lo cells did not yield TCF-1hi cells. To test the role of TCF-1, we studied CD8 cells lacking long TCF-1 isoforms (p45-/-). P45-/- cells were outcompeted by WT cells when transplanted into 129 recipients, though they expanded similarly in syngeneic recipients. In the B6→C3H.SW(H-2b) model, p45-/- CD8 cells caused less weight loss than did WT CD8 cells; however, histopathologic GVHD was similar in both groups. P45-/- and WT CD8 cells also had similar graft versus leukemia activity. These results highlight the complex biology of TCF-1 in supporting alloreactive T cell function.
    Keywords:  Adaptive immunity; Bone marrow transplantation; Immunology; T cells; Transplantation
    DOI:  https://doi.org/10.1172/jci.insight.181568
  9. iScience. 2025 Oct 17. 28(10): 113538
    Macrophage repolarization by immune checkpoint blockade drives T cell engagement in the tumor microenvironment.
    Tina Kwok, Ildefonso A Silva-Junior, Sara Korpe, Haidong Dong, Jessica N Lancaster.
      Immunotherapy combinations can improve patient outcomes, yet the interactions within the tumor microenvironment (TME) that drive therapeutic synergy are poorly understood. Tumor establishment drives monocyte recruitment and differentiation into tumor-associated macrophages (TAMs), which have essential roles in coordinating immune responses and are thus attractive targets for therapeutic modulation. In a murine model of combination anti-programmed cell death protein 1 (PD-1) and its ligand (anti-PD-L1) checkpoint blockade, tumor control was associated with increased infiltration of CD8+ T cells and M1-like repolarization of TAMs. Live-cell imaging of the tumor microenvironment revealed close contacts between tumor-infiltrating CD8+ T cells and TAMs, in which the extent of the contact interfaces increased with combination immunotherapy. Treatment with anti-PD-L1 was able to increase macrophage expression of pro-inflammatory factors and phagocytic activity, suggesting a role for TAMs in reactivating CD8+ T cells in the TME. However, co-treatment with anti-PD-1 was ultimately necessary for tumor control, indicating the need for combination targeting of the TME.
    Keywords:  Cancer; Immunology; Microenvironment
    DOI:  https://doi.org/10.1016/j.isci.2025.113538
  10. Circulation. 2025 Oct 07. 152(14): 1023-1025
    NK-Like CD8+ T Cells: Professional Assassins in Fulminant Myocarditis.
    Saidi A Mohiddin, Federica M Marelli-Berg.
      
    Keywords:  CD8+ T cells; Editorials; acute heart failure; macrophages; myocarditis
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.125.075849
  11. J Drug Target. 2025 Oct 08. 1-25
    DNAJA1 as a Modulator of CD8+ T-Cell Function and Prognosis in Lung Cancer: Implications for Immune Regulation and Therapeutic Targeting.
    Shengkai Yang, Lian Liu, Yubiao Guo, Luqi Dai.
      In lung adenocarcinoma (LUAD), dysfunctional CD8+ T-cells and an immunosuppressive tumour microenvironment (TME) are major barriers to effective immunotherapy, yet the molecular regulators coordinating T cell exhaustion and macrophage polarization remain undefined. To address this, we integrated single-cell RNA sequencing, TCGA transcriptome and methylation data, co-culture assays, chromatin profiling, functional assays, and xenograft models to investigate the role of DNAJA1 in immune regulation and tumor progression. Our results demonstrated that DNAJA1 was upregulated in exhausted CD8+ T-cells in lung cancer tissues and correlated positively with exhaustion markers including PD-1, TIM-3, and LAG-3. Notably, exhausted CD8+ T-cells exhibited DNAJA1 promoter hypomethylation and enrichment of activating histone modifications H3K4me3 and H3K27ac, while inhibiting the activation of H3K4me3 and H3K27ac reduced DNAJA1 expression. Additionally, DNAJA1 overexpression upregulated M2-associated genes (CD206 and IL-10), while its knockdown enhanced the expression of M1-associated genes (CD86 and IL-12). Furthermore, DNAJA1 promoted tumour cell proliferation, and its expression level showed a moderate positive correlation with PD-L1. Collectively, these findings establish DNAJA1 as an epigenetically activated regulator that drives CD8+ T-cell exhaustion and protumor macrophage polarization, highlighting its dual role as a functional immunomodulator and potential biomarker for stratifying LUAD patients with immune-dysregulated TME.
    Keywords:  CD8 + T-cells; DNAJA1; Immune microenvironment; Lung cancer; Single-cell RNA sequencing
    DOI:  https://doi.org/10.1080/1061186X.2025.2571546
  12. J Transl Med. 2025 Oct 06. 23(1): 1055
    Deciphering metabolic reprogramming of immune cells within the tumor microenvironment.
    Yinping Wang, Weijie Chen, Zida Wang, Siwen Cai, Xinnan Zhao, Jingsi Jin, Ting Gao, Junwen Qu.
       BACKGROUND: Immunometabolic adaptations may induce tumor immune escape and immunotherapeutic resistance, representing crucial mechanisms in cancer progression. Understanding the metabolic rewiring of tumor-infiltrating immune cells as tumors advance could enhance current immune-oncology treatments.
    METHODS: In this study, we investigated metabolic heterogeneity in immune cells within both tumor and adjacent normal tissue using single-cell transcriptome profiling of colon cancer. We also utilized the MC38 colorectal cancer model, a commonly employed mouse tumor model, to assess the metabolic atlas of major immune cell populations in tumor and normal tissue.
    RESULTS: We examined the immunometabolic features in tumor tissue and adjacent normal tissue using public single-cell transcriptomic datasets of colorectal cancer (CRC) patients, in which myeloid cells showed dominant metabolic activity. Using a mouse tumor model, we demonstrated distinct metabolic reprogramming of major immune cell types in tumor compared to normal tissue. Specifically, we observed increased glucose and lipid uptake, along with abundant lipid accumulation in tumor-infiltrating myeloid cells, particularly macrophages. Additionally, we identified diverse mitochondrial fitness and oxidative stress levels within the tumor immune microenvironment. Macrophages exhibited metabolic fitness, CD8+ T cells displayed mitochondrial depolarization, and neutrophils showed high oxidative stress. Furthermore, we investigated immunometabolic dynamics and observed augmented metabolic activity in immune cells infiltrating progressive and late stages of tumor development. Notably, intratumoral macrophages exhibited metabolic heterogeneity, characterized by robust lipid uptake and synthesis, which correlated with a pro-tumor phenotype and poor clinical outcomes.
    CONCLUSION: Overall, our study unveils the heterogeneity and dynamics of metabolic properties in immune cells within the tumor microenvironment. These findings provide insights for developing therapeutic strategies that target metabolism to enhance antitumor immunity.
    Keywords:  Colon cancer; Immune metabolism; Tumor microenvironment; Tumor-associated macrophage
    DOI:  https://doi.org/10.1186/s12967-025-07069-y
  13. Cell Mol Gastroenterol Hepatol. 2025 Oct 01. pii: S2352-345X(25)00172-9. [Epub ahead of print] 101631
    Ferroptosis: A Novel Target to Rescue CD8+ T Cells Against Hepatitis B Virus.
    Yongyan Chen.
      
    DOI:  https://doi.org/10.1016/j.jcmgh.2025.101631
  14. Cell Death Dis. 2025 Oct 06. 16(1): 679
    Comprehensive characterisation of age-related changes in cell subpopulations and tissue structural properties in secondary lymphoid organs.
    Yuxin Deng, Xin He, Juzheng Peng, Yuxi Pan, Yusheng Luo, Yueheng Ruan, Jianfeng Hou, Bangxue Jiang, Xiangyu Li, Xiaomei Liang, Jiayuan Huang, Jiancheng Wang.
      Population aging is an escalating global phenomenon, wherein age-related alterations in the human immune system exacerbate the susceptibility to diseases including infections and autoimmune disorders. Secondary lymphoid organs (SLOs) are key locations for the execution of immunological responses by mature immune cells; however, age-related changes in SLOs remain relatively understudied. To address this gap, this study employed comprehensive approaches including single-cell RNA sequencing (scRNA-seq) data analysis, immunofluorescence staining, flow cytometry, and morphological analysis, to clarify the age-related alterations in SLOs in mice. The results demonstrated that aging caused senescent immune cells to accumulate and subpopulations to reorganize, with a decrease in the proportion of naïve T cells, whilst an increase in regulatory T (Treg) cells, cytotoxic T lymphocytes (CTLs), and exhausted T (Tex) cells. Notably, CD4+ and CD8+ T cells exhibited distinct senescence patterns in Peyer's patches, suggesting tissue-specific responses to aging, which may arise from differential exposure to gut microbiota. In addition to the alterations in immune cell populations, we also identified increased stromal cell senescence and altered distributions of marginal reticular cells and follicular dendritic cells, which may further contribute to age-related immune dysfunction. Finally, examining SLO structural features, including size, fibrosis, stiffness, and pigmentation, revealed degenerative changes that impair immune function. Collectively, this study will assist with the development of strategies aimed at delaying aging and treating age-related diseases.
    DOI:  https://doi.org/10.1038/s41419-025-08007-y
  15. ACS Nano. 2025 Oct 07.
    Mito-Specific "Trojan Horse" Nanotherapy: Synergistic Antitumor Immunotherapy via Dual Modulation Mitochondrial Metabolism and Glycolysis.
    Jingjing Yang, Mingyang Li, Zhao Wei, Jin Qian, Maoquan Chu, Zhe Qiang, Jie Ren.
      Metabolic reprogramming enables tumor cells to survive and proliferate in a nutrient-deficient environment. However, the immunosuppressive tumor microenvironment caused by metabolic reprogramming is often overlooked in current metabolism interventions. Herein, we developed a mito-specific "Trojan Horse" nanoplatform (2-pN@LNPs) coloaded with Niclosamide (Nic) and 2-deoxy-d-glucose (2-DG) to attack key metabolism pathways and synergistically ignite pyroptosis for restoring antitumor immunity. 2-pN@LNPs promoted proton influx across the inner mitochondrial membrane and caused oxidative phosphorylation (OXPHOS) into a futile cycle. Furthermore, 2-pN@LNPs exploited the increased glucose demand to deliver the glycolysis inhibitor 2-DG, causing metabolic network collapse. Both cell and three-dimensional multicellular tumor spheroid results demonstrated superior synergistic metabolic intervention efficacy. The multipath metabolism deprivation leads to irreversible mitochondrial dysfunction, followed by excessive reactive oxygen species accumulation, severe adenosine triphosphate loss, and ultimately exerted a pyroptosis-like micromorphology. Moreover, the synergistic treatment regimen can promote cytotoxic and helper T cells (CD8+/CD4+ T cells) recruitment and M1-type macrophage polarization, facilitating the establishment of a boost in immunological memory to prevent recurrence and metastasis. Overall, this work provides a robust strategy targeting metabolism through mitochondrial uncoupling and glycolysis inhibition, which can effectively improve the antitumor effect, inhibit lung metastasis, and help modulate antitumor immunity.
    Keywords:  antitumor immunity; glycolysis inhibition; metabolic reprogramming; mitochondrial uncoupling; mitochondrial-targeted therapy
    DOI:  https://doi.org/10.1021/acsnano.5c08486
  16. Blood. 2025 Oct 09. 146(15): 1742-1744
    Smarter combos, stronger T cells in lymphoma.
    Santosha A Vardhana.
      
    DOI:  https://doi.org/10.1182/blood.2025030331
  17. Front Immunol. 2025 ;16 1656692
    Extracellular vesicles of patients with acute-on-chronic liver failure induce mitochondrial dysfunction in T cells.
    Mona-May Langer, Sabrina Guckenbiehl, Alina Bauschen, Helena Stadler, Farnusch Kaschani, Markus Kaiser, Bernd Walkenfort, Heiner Wedemeyer, Christian M Lange.
       Background and Aims: Liver cirrhosis and in particular acute-on-chronic liver failure (ACLF) are characterized by systemic inflammation and dysfunctional immune responses. Extracellular vesicles (EVs) are important mediators of cell stress and inflammation, but their role in ACLF is unclear.
    Methods: Phenotype and immune function of EVs of patients with compensated liver cirrhosis, acute decompensation, or ACLF were characterized regarding particle size, concentration, surface markers, and RNA cargo. In addition, functional analyses were performed to assess the impact of EVs on T cells.
    Results: EVs of patients with liver cirrhosis showed lower expression of exosome-specific markers (e.g. CD9, CD63, CD81) than EVs of healthy individuals, carried a distinct cargo of proteins and small RNAs, and were in high frequency derived from liver cells based on their carriage of liver cell markers such as ASGPR1, CD248 or CD163. Of note, in ACLF the concentration of EVs decreased, and EVs in ACLF lost partially their differentiation and surface markers but were enriched in lncRNAs. In functional assays, EVs of patients with cirrhosis and ACLF induced changes in the composition of T cell populations like a loss of naïve and central memory T cells and an increase in effector memory T cells. Mechanistically, EVs decreased the viability of CD3+ T cells, which could be explained by an induction of mitochondrial dysfunction.
    Conclusion: Liver cirrhosis is associated with distinct changes in circulating EVs. In ACLF, EVs are less differentiated and induce mitochondrial dysfunction, decreased T cell viability and changes in the composition of T cell populations.
    Keywords:  T cell exhaustion; exosomes; liver cirrhosis; organ failure; systemic inflammation
    DOI:  https://doi.org/10.3389/fimmu.2025.1656692
  18. Immunology. 2025 Oct 08.
    Molecular Mediators of Metabolic Reprogramming in Cancer: Mechanisms, Regulatory Networks, and Therapeutic Strategies.
    Sana Ahuja, Sufian Zaheer.
      Metabolic reprogramming is a hallmark of cancer, enabling tumour cells to flexibly adapt to fluctuating microenvironmental conditions, sustain uncontrolled proliferation, and acquire resistance to conventional therapies. Tumour metabolism is not limited to the classical Warburg effect but encompasses a dynamic interplay between glycolysis, oxidative phosphorylation (OXPHOS), fatty acid metabolism, and amino acid utilisation, each fine-tuned according to tissue context, tumour type, and stage of progression. Central regulators such as hypoxia-inducible factor-1 (HIF-1), MYC, p53, peroxisome proliferator-activated receptors (PPARs), oestrogen receptor (ER), and sterol regulatory element-binding proteins (SREBPs) orchestrate these pathways, linking nutrient availability to oncogenic signalling and transcriptional control. This review synthesises current evidence on these interconnected metabolic circuits and critically evaluates existing controversies, such as the dual reliance on glycolysis and OXPHOS, metabolic plasticity under therapeutic pressure, and the role of stromal-tumor metabolic crosstalk. Beyond established pathways, emerging areas are transforming our understanding of tumour metabolism. Single-cell metabolic profiling and spatial metabolomics reveal profound intratumoral heterogeneity, while immunometabolism highlights the bidirectional influence of cancer cells and immune cells within the tumour microenvironment (TME). Epigenetic regulation, driven by metabolites that serve as cofactors for chromatin-modifying enzymes, further integrates metabolic states with transcriptional reprogramming and therapy response. Translationally, targeting metabolic dependencies remains challenging; promising therapeutic opportunities are being developed, including inhibitors of lactate transporters, fatty acid oxidation, and glutamine metabolism. This review integrates mechanistic insights with translational perspectives, providing conceptual models, summary tables, and schematic illustrations to clarify complex networks and highlight clinically relevant opportunities. By mapping the evolving landscape of cancer metabolism, we aim to illuminate both the challenges and the therapeutic potential of exploiting metabolic vulnerabilities in oncology.
    Keywords:  OXPHOS; glycolysis; mediators; metabolic reprogramming; tumour microenvironment
    DOI:  https://doi.org/10.1111/imm.70045
  19. Front Immunol. 2025 ;16 1675677
    Microbial metabolites and their influence on the tumor microenvironment.
    Huanglin Duan, Baisheng Xu, Peiyue Luo, Tao Chen, Jun Zou.
      While tumor immunotherapy has achieved remarkable progress in many hematological malignancies, its efficacy remains limited by key challenges, including the immunosuppressive microenvironment of solid tumors, metabolic abnormalities, and drug resistance. As a central mechanism underlying impaired immune function, metabolic reprogramming of immune cells has emerged as a pivotal focus for unraveling tumor immune evasion and therapeutic resistance. Advances in metagenomics have highlighted the significance of the human commensal microbiome as a 'second genome.' Microbial metabolites, whether circulating systemically or accumulating locally, serve as key messengers linking the microbiota to tumor immunometabolism. This review comprehensively examines the regulatory roles and metabolic mechanisms through which microbial metabolites-including short-chain fatty acids (SCFAs), bile acids, tryptophan metabolites, and lipopolysaccharides (LPS)-modulate tumor immunity and immunotherapeutic responses via immune cell metabolism. These metabolites shape the tumor immune microenvironment and influence immunotherapeutic efficacy by reprogramming immune cell metabolic and biosynthetic pathways. This review underscores the central regulatory role of microbial metabolites as the 'second genome' in tumor immunometabolism, offering a theoretical foundation and potential targets to elucidate mechanisms of immunotherapeutic resistance and advance microbiota metabolism-based precision interventions.
    Keywords:  immunometabolism; immunotherapy; microbial metabolites; tumor immunity; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1675677
  20. J Allergy Clin Immunol. 2025 Oct 07. pii: S0091-6749(25)00973-X. [Epub ahead of print]
    Selective IL-2 delivery modulates CD8+ T cells in human HLH and ameliorates disease features in a murine model.
    Tommaso Marchetti, Samantha Milanesi, Diana Tintor, Julius Köppen, Tiziana Lorenzini, Severin Walser, Stefano Vavassori, Onur Boyman, Jana Pachlopnik Schmid.
      
    Keywords:  HLH; IL-2; T cell; cytokine complexes; cytotoxicity
    DOI:  https://doi.org/10.1016/j.jaci.2025.09.009
  21. Neuro Oncol. 2025 Oct 11. pii: noaf240. [Epub ahead of print]
    CAR T cell therapy for meningioma: mesothelin emerges as a novel promising target.
    Denis Migliorini.
      
    DOI:  https://doi.org/10.1093/neuonc/noaf240
  22. Aging Cell. 2025 Oct 06. e70252
    Age-Associated Expansion of HIV/SIV Reservoirs in People With HIV and SIV-Infected Macaques.
    Arpan Acharya, Debapriya Sutar, Mahesh Mohan, Varan Govind, Francois Villinger, Suresh Pallikkuth, Siddappa N Byrareddy.
      With the advancement of combination antiretroviral therapy (ART), over 50% of people with HIV (PWH) in the United States are now over the age of 50. A hallmark of the aging immune system is a progressive dysfunction of both the innate and adaptive immune responses, often characterized by clonal expansion of memory T cells. However, the impact of age-related immune dysfunction on HIV/SIV reservoir dynamics remains understudied. We hypothesized that age-associated clonal expansion of memory T cells contributes to the increase of the HIV reservoirs in older PWH (OPWH). In this retrospective study, we utilized archived peripheral blood mononuclear cells (PBMCs) from young and older PWH with suppressed plasma viremia for at least 5 years and quantified both intact and total HIV proviral DNA from CD4+ T cells. Alongside the human study, we also analyzed samples from SIV-infected, ART-suppressed young and aged rhesus macaques, quantifying intact and total proviruses in CD4+ T cells. We observed a significantly higher level of intact and total proviral DNA in older compared to younger PWH. The frequency of intact provirus was positively correlated with activated CD4+ and CD8+ T cells. Consistently, in the non-human primate model, aged macaques exhibited significantly higher levels of intact and total SIV proviruses in CD4+ T cells than their younger counterparts. Collectively, these findings suggest that the HIV/SIV reservoir expands with age, potentially driven by immune activation. Future studies are warranted to elucidate the mechanisms underlying reservoir expansion in the aging population.
    Keywords:  CD4+ T cells; antiretroviral therapy (ART); human immunodeficiency virus‐1 (HIV); intact proviral DNA; people living with HIV (PWH); reservoirs; simian immunodeficiency virus (SIV)
    DOI:  https://doi.org/10.1111/acel.70252
  23. Cell Commun Signal. 2025 Oct 10. 23(1): 431
    T cell receptor associated transmembrane adaptor 1 (TRAT1) modulates human Th17 and Treg responses via PI3-kinase and STAT dependent mechanisms.
    Tobias Frey, Christina Kandolf-Zumpf, Anna Kaempf, Kristin Schaffer, Marlene Hollenstein, Annika Lampl, Johannes J Kovarik, Johanna Strobl, Georg Stary, Julia Eckl-Dorna, Ralf Schmidt, Klaus G Schmetterer.
       BACKGROUND: Adaptor proteins associated with the T cell receptor (TCR) play critical roles in regulating immune responses by Translating receptor engagement into intracellular signals. T cell Receptor Associated Transmembrane Adaptor 1 (TRAT1) has been implicated in modulating TCR complex stability, but its functional role in human effector and regulatory CD4⁺ T cell subsets remains poorly understood. This study aimed to elucidate the role of TRAT1 in regulating T cell activation and differentiation, particularly in helper T cells function and regulatory T cells.
    METHODS: Primary human CD4⁺ T cells, including thymus-derived and induced regulatory T cells (Treg), were genetically modified by CRISPR/Cas9-mediated gene deletion or retro-/lentiviral overexpression of TRAT1. Functional assays, flow cytometry, cytokine quantification, and RNA sequencing were performed to evaluate modulation of T cell functions. Mechanistic studies included pathway inhibition using small molecules and phospho-protein analysis. The influence of TRAT1 on Treg function was further assessed in a CAR Treg context in an immune organoid model of allo-rejection.
    RESULTS: Thymus-derived, TGFb-induced and FOXP3-transgenic Treg displayed reduced expression of TRAT1 compared to effector T cells, which showed pronounced up-regulation of TRAT1 following activation. In effector T cells, deletion of TRAT1 led to increased signaling through the phosphoinositide 3-kinase pathway resulting in enhanced proliferation and increased expression of activation markers. However, this was accompanied by reduced production of interleukin-17, which was linked to elevated activity of STAT6 as shown by inhibition experiments using small molecule inhibitors. Overexpression and CRISPR/Cas9-mediated knockout of TRAT1 in Treg enhanced suppression of CD4⁺ target cells via up-regulation of LAP/GARP but reduced suppression of CD8⁺ target cells, an effect confirmed in HLA-A2-specific CAR Treg in a human organoid model of allo-rejection.
    CONCLUSIONS: TRAT1 acts as a dual regulator of human CD4⁺ T cell function, limiting effector activation through modulation of intracellular signaling and supporting regulatory T cell-mediated suppression. These findings reveal a novel mechanism of immune regulation with potential implications for the development of cell-based immunotherapies.
    Keywords:  Adaptor molecules; CAR treg; T cell receptor; T cell signaling; Th17
    DOI:  https://doi.org/10.1186/s12964-025-02429-z
  24. Nat Protoc. 2025 Oct 09.
    Manufacturing synthetic viscoelastic antigen-presenting cells for immunotherapy.
    Zeyang Liu, Yan-Ruide Li, Youcheng Yang, Enbo Zhu, Haochen Nan, Yue Yan, Bo Zhang, Guorui Chen, Nicolas Pedroncelli, Zibai Lyu, Jason Lin, Jennifer Soto, Lili Yang, Song Li.
      This protocol details the preparation and functionalization of viscoelastic synthetic antigen-presenting cells (APCs) for T cell activation, designed to enhance immunotherapeutic efficacy. Using a high-throughput microfluidic system and post-processing, we create cell-sized sodium alginate microbeads with tunable stiffness, viscoelasticity and surface chemistry, enabling them to better mimic the physical and activation properties of natural APCs. The protocol includes fabrication of synthetic cells with defined sizes, crosslinking strategies to achieve desirable mechanical properties, surface functionalization via click chemistry for attaching activation molecules, and characterization methods for mechanical and biochemical properties. Compared with traditional matrices or rigid microbeads, this approach allows precise control over the mechanical and biochemical features of synthetic APCs, ensuring optimal T cell activation. The resulting synthetic cells support robust T cell activation and expansion, enhance the CD8/CD4 T cell ratio, promote T memory stem cell (TMSC) formation and improve chimeric antigen receptor transduction efficiency, leading to superior tumor-killing efficacy in vitro and in vivo. Additionally, these synthetic cells can be efficiently removed from T cells after activation using simple centrifugation or calcium chelation, preserving the activated T cells. The complete protocol, including fabrication, functionalization and quality assessment, requires ~1 week to complete. Users should have experience in microfluidics, biomaterial handling, bioconjugation techniques and basic cell culture. This platform can be adapted for broader applications in immune cell engineering.
    DOI:  https://doi.org/10.1038/s41596-025-01265-2
  25. Blood. 2025 Oct 07. pii: blood.2024026505. [Epub ahead of print]
    A Notch trans-activation to cis-inhibition switch underlies hematopoietic stem cell aging.
    Francesca Matteini, Roshana Thambyrajah, Sara Montserrat-Vazquez, Sascha Jung, Alba Ferrer-Perez, Patricia Herrero Molinero, Dina El Jaramany, Javier Lozano-Bartolomé, Eva Mejia-Ramirez, Jessica Gonzalez Miranda, Antonio Del Sol, Anna Bigas, Maria Carolina Florian.
      Aged hematopoietic stem cells (HSCs) expand in clusters over time, while reducing their regenerative capacity and their ability to preserve the homeostasis of the hematopoietic system. The expression of Notch ligands in the bone marrow (BM) niche is essential for hematopoiesis. However, the impact of Notch signaling for adult HSC function and its involvement in HSC aging remains controversial. Here we show that Notch activation in young HSCs is not homogeneous, and it is triggered by sinusoidal expression of the Notch ligand Jagged2 (Jag2). Sinusoidal Jag2 deletion in young mice recapitulates the decrease in Notch activity observed in aged HSCs and alters HSC divisional symmetry and fate priming, promoting myeloid-biased HSCs (My-HSCs) expansion. Mechanistically, our data reveals that upon decreasing sinusoidal Jag2 expression, HSCs themselves upregulate Jag2, which cis-inhibits Notch signaling, resulting in the expansion of My-HSCs and in reduced hematopoietic regeneration. Collectively, these findings identify the crosstalk between BM niche-driven and HSC intrinsic features in regulating HSC fate priming and regenerative potential and reveal an extrinsic Notch trans-activation to intrinsic cis-inhibition switch underlying HSC aging.
    DOI:  https://doi.org/10.1182/blood.2024026505
  26. Nat Cardiovasc Res. 2025 Oct 07.
    Progenitor exhausted PD-1+ T cells are cellular targets of immune checkpoint inhibition in atherosclerosis.
    Megan Mulholland, Anthi Chalou, Samuel H A Andersson, Marie A C Depuydt, Yinda Yu, Shiying Lin, Klara Tallbäck, Astrid Ericsson, Gabriel Jakobsson, Jill de Mol, Dmytro Kryvokhyzha, Andrew H Lichtman, Amanda C Foks, Alexandru Schiopu, Harry Björkbacka, Bram Slütter, Anton Gisterå, Daniel Engelbertsen.
      Immune checkpoint inhibitors (ICIs), targeting checkpoint receptors such as programmed cell death protein 1 (PD-1), are associated with increased risk of cardiovascular events, but the underlying mechanisms remain poorly understood. Here we show that PD-1+ T cells from murine atherosclerotic aortas mainly display a progenitor exhausted phenotype (PD-1intSlamf6+Tim3-), produce IFNγ in vivo, exhibit signs of recent proliferation and maintain polyfunctionality. PD-1 blockade induced marked changes in plaque immune phenotype, with increased PD-1high T cell accumulation, IFNγ production, formation of lymphocyte foci and neutrophil recruitment. Depletion of PD-1high T cells prior to PD-1 blockade did not impede T cell recruitment, suggesting a role for progenitor exhausted PD-1int T cells in ICI-driven T cell plaque accumulation. Human circulating PD-1+ T cells produced IFNγ and were associated with subclinical coronary atherosclerosis. Our studies highlight IFNγ-producing PD-1+ T cells as a potential key immune cell population mediating increased cardiovascular risk in patients with cancer receiving ICI.
    DOI:  https://doi.org/10.1038/s44161-025-00713-2
  27. Int J Biol Macromol. 2025 Oct 05. pii: S0141-8130(25)08664-7. [Epub ahead of print] 148107
    HRS sustains mitochondrial homeostasis by anchoring destabilized proteins during tumorigenesis.
    Bo-Lin Xiao, Jin-Bang Li, Zhuo-Kun Chen, Ze-Chen Zhao, Yi-Man Wang, Hai-Ming Liu, Hou-Fu Xia, Qiu-Yun Fu, Shao-Xin Huang, Jun Shang, Gang Chen, Wei Zhang.
      The role of the endosomal sorting complex required for transport (ESCRT) in tumorigenesis remains controversial and context-dependent, with its subunits often exhibiting opposing functions across cancer types. The ESCRT-0 component HRS (hepatocyte growth factor-regulated tyrosine kinase substrate) has been linked to both tumor-suppressive and pro-oncogenic processes, yet its impact on tumor initiation and metabolic adaptation is poorly understood. Here, using a transgenic melanoma model, we demonstrate that melanocyte-specific deletion of HRS delays tumor onset, suppresses tumor growth, and prolongs survival. HRS-deficient tumor cells exhibit a shift toward glycolytic metabolism and impaired proliferation under energy stress. We further show that HRS loss leads to mitochondrial dysfunction, marked by disrupted morphology, reduced tricarboxylic acid (TCA) cycle metabolites, and decreased respiratory enzyme levels. Mechanistically, HRS deficiency disrupts the FYVE- and UIM domain-dependent endosomal clearance of ubiquitinated misfolded proteins, leading to their translocation into mitochondria. This aberrant accumulation triggers a mitochondrial unfolded protein response (mtUPR) and compromises mitochondrial function. Clearance of misfolded proteins from mitochondria rescues these defects. Our study reveals a non-canonical role for HRS in maintaining mitochondrial proteostasis and supporting tumor metabolic plasticity, highlighting HRS as a potential target for disrupting tumor metabolic adaptation.
    Keywords:  HRS; Mitochondrion; Tumorigenesis
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.148107
  28. Nat Commun. 2025 Oct 08. 16(1): 8952
    Metabolic profiling reveals channeled de novo pyrimidine and purine biosynthesis fueled by mitochondrially generated aspartic acid in cancer cells.
    Vidhi Pareek, Stephen Benkovic.
      Cancer cells have the unique capability to upregulate the de novo nucleotide biosynthesis supporting cell survival under nucleotide deprivation. We probe the role of metabolic channeling and membrane-less metabolic compartmentalization by mitochondria-proximal dynamic de novo pyrimidine and purine biosynthesis metabolons, the pyrimidinosome and the purinosome, respectively. We designed in-cell stable isotope label incorporation assays (13C6 glucose, 15N2 glutamine) for detection of metabolic channeling, revealing the function and enzymatic composition of these complexes. Moreover, we discovered that the mitochondrially compartmentalized GOT2 dependent generation of aspartic acid feeds the channeled nucleotide synthesis instead of the bulk cytosolic pool or the GOT1 activity. While a low flux diffusive pathway generates the pathway intermediates in an accumulative process, it's the channeled pathway that successfully generates the end product nucleotides. Our results demonstrate how metabolic channeling and efficient de novo nucleotide biosynthesis is fueled by coordination of mitochondrially compartmentalized metabolic events with cytosolic metabolons in cancer cells.
    DOI:  https://doi.org/10.1038/s41467-025-64013-w
  29. Eur J Immunol. 2025 Oct;55(10): e70070
    Purin Metabolism Is Crucial for Regulatory T Cell Stability and Function.
    Young S Lee, Marina W Shirkey, Vikas Saxena, Dejun Kong, Bing Ma, Reza Abdi, Jonathan S Bromberg.
      Cellular metabolism intricately directs the differentiation, stability, and function of regulatory T cells (Tregs), which are pivotal in immune regulation. Metabolic reprogramming enables Tregs to adapt to diverse tissue environments; however, it can also disturb immune equilibrium, driving their conversion into unfavorable states like exTregs that hinder regulation in autoimmunity and transplantation. Purine metabolism has emerged as a critical but underexplored regulator of Treg biology. Beyond their traditional roles in nucleotide synthesis and energy balance, purine metabolites also serve as potent second messengers shaping Treg phenotype, suppressive capacity, and adaptability in inflammatory, autoimmune, and transplant environments. Extracellular ATP promotes inflammation, while adenosine supports Treg-mediated immunosuppression, highlighting a dual and context-dependent nature of purinergic signaling. This review outlines current findings on intracellular and extracellular purine metabolism in Tregs, emphasizing key enzymes and purinergic receptors that sustain Treg phenotype and resilience. It discusses disruptions in purine signaling compromising Treg functions, identifies knowledge gaps, and proposes future research directions for potential therapeutic strategies in immune-related ailments.
    Keywords:  Treg stability; exTregs; purine metabolism; purinergic receptors; regulatory T cells (Tregs)
    DOI:  https://doi.org/10.1002/eji.70070
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