bims-imseme 2025-11-09 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2025–11–09
27 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Beyond Energy Fuel: Ketone Bodies as Multifaceted Modulators of T Cell and Anti-Tumour Immunity.
Epigenetic regulation of CD8+ T cell exhaustion: recent advances and update.
How T cells handle lipids.
Metabolic modulation of CD8⁺ T cells by metformin: A promising adjuvant strategy for CD8⁺ T Cell-Based Immunotherapies.
Defining Microbiota-Derived Metabolite Butyrate as a Senomorphic: Therapeutic Potential in the Age-Related T Cell Senescence.
Role of oxygen sensing and hypoxia-inducible factors in orchestrating innate immune responses.
Ascorbic acid attenuates immunosenescence and cognitive decline via MYH9-Mediated CD8⁺ T cell differentiation.
Multi-modal single-cell platform for nanoparticle-enhanced time-series metabolic profiles of CD8+ T cell exhaustion in tumor immunosurveillance.
Epigenetically Controlled ZEB2 Expression Promotes the Cytotoxic Potential of CMV-Specific CD8+ T Cells.
Tumor-Associated Macrophages Produce PGE2 to Promote CD8+ T Cell Exhaustion and Drive Resistance to PD-L1 Blockade in Microsatellite Stable Colorectal Cancer.
Protocol for halofuginone-mediated metabolic reprogramming of murine T cells via activation of the GCN2 pathway.
A natural compound revitalizes the aging human immune system.
Mass cytometric analysis of circulating immune landscape in primary central nervous system lymphoma.
Drug-loaded bispecific T cell nanoengager overcomes T cell exhaustion for potent cancer immunotherapy.
Proteomic signatures and mitochondrial dysfunctions in peripheral T cells reveal novel ınsights into Alzheimer's disease.
Aging represses oncogenic KRAS-driven lung tumorigenesis and alters tumor suppression.
Cancer-associated adipocytes mediate CD8+T cell dysfunction via FGF21-driven lipolysis.
Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function.
Increased CD103-CD8+ TILs with TPEX phenotype replenish anti-tumor T cell pool in mismatch repair-proficient CRC.
Metabolic reprogramming of immune cells in the battle against intracellular bacterial chronic infections: novel mechanisms and breakthroughs.
Value of CD8+ T cell-related genes and IL-6/STAT3 signaling pathway in the prognosis of HCC and experimental investigation.
Circulating interleukin-18 drives expansion of pathogenic CD57+CD8+ T cells in acute myocarditis.
Microbiota-derived butyrate promotes a FOXO1-induced stemness program and preserves CD8+ T cell immunity against melanoma.
Differentiated T Lymphocytes and Cancer Cell Mitochondrial Metabolism to Enhance Radioimmunotherapy by a Biomimetic Nanozyme System.
Metabolic reprogramming through PIM3 inhibition reverses hypoxia-induced CAR-T cell dysfunction in solid tumors.
NUDT5 regulates purine metabolism and thiopurine sensitivity by interacting with PPAT.
Spermidine Remodels the Mitochondrial Metabolism of Tumor-Infiltrating Lymphocytes.

Scand J Immunol. 2025 Nov;102(5): e70067

Beyond Energy Fuel: Ketone Bodies as Multifaceted Modulators of T Cell and Anti-Tumour Immunity.

Zhi Gu, Minghui Zhang, Sheng Xia.

  The metabolic programme of T cells is pivotal in determining their differentiation, development and immune function. T cells undergo distinct metabolic reprogramming at various stages. Effector T cells primarily utilise glycolysis to generate energy quickly, whereas memory T cells depend on fatty acid oxidation (FAO) to sustain long-term survival and enable rapid reactivation. This metabolic differentiation is regulated through metabolic reprogramming by adjusting nutrient utilisation to meet specific demands. Ketone bodies, FAO-derived metabolites, interact with glucose and amino acid metabolism to influence the function and differentiation of T cells and other immune cell subsets. The body's metabolic equilibrium is significantly influenced by dietary patterns. A medically designed dietary intervention that elevates ketone body levels can reshape T-cell metabolism, influencing their differentiation, development and immune functions. This metabolic modulation suggests a potential interplay between nutritional strategies and T-cell immunotherapy applications, especially in the context of tumour immunology. This review explores ketone body metabolism and its impact on T-cell function, offering insights into the clinical use of diet-induced ketosis for T-cell immunotherapy. It also emphasises the potential of metabolic reprogramming to boost T cell performance and improve the efficacy of immunotherapy.

Keywords:  T cell; immunotherapy; ketone body; ketone diet; metabolism

DOI:  https://doi.org/10.1111/sji.70067
Front Immunol. 2025 ;16 1700039

Epigenetic regulation of CD8+ T cell exhaustion: recent advances and update.

Chunhong Li, Yixiao Yuan, Xiulin Jiang, Qiang Wang.

  CD8+ T cells play a pivotal role in antiviral and antitumor immunity, yet under chronic antigen stimulation, they progressively enter a functionally impaired "exhausted" state, characterized by loss of effector functions, sustained high expression of inhibitory receptors, and a distinct transcriptional and epigenetic landscape. Recent studies have highlighted that epigenetic regulation is central to the initiation and maintenance of CD8+ T cell exhaustion. Exhausted T cells exhibit chromatin landscapes markedly different from those of effector and memory T cells, displaying an "epigenetic locking" that renders their phenotype largely irreversible. Emerging evidence highlights the central role of epigenetic and transcriptional regulation in driving and maintaining CD8+ T cell exhaustion. DNA methylation and histone modifications establish stable repressive chromatin landscapes that suppress effector gene programs. Non-coding RNAs, including microRNAs and long non-coding RNAs, fine-tune exhaustion-associated pathways post-transcriptionally, while RNA epigenetic modifications, such as m6A methylation, regulate transcript stability and translation in exhausted T cells. Transcription factors orchestrate these epigenetic and post-transcriptional networks, reinforcing exhaustion-specific gene expression profiles. Together, these interconnected mechanisms not only define the exhausted phenotype but also contribute to tumor immune evasion and therapeutic resistance. Understanding these processes provides a framework for novel strategies aimed at reversing CD8+ T cell exhaustion and improving the efficacy of cancer immunotherapy. Collectively, elucidating the epigenetic mechanisms underlying CD8+ T cell exhaustion not only deepens our understanding of its molecular basis but also provides new avenues for precision immunotherapy and individualized interventions.

Keywords:  CD8+ T cell exhaustion; DNA methylation; epigenetic regulation; histone modification; immunotherapy; transcription factors

DOI:  https://doi.org/10.3389/fimmu.2025.1700039
Nat Rev Immunol. 2025 Nov 06.

How T cells handle lipids.

Lucy Bird.

DOI: https://doi.org/10.1038/s41577-025-01242-6
Pharmacol Res. 2025 Oct 30. pii: S1043-6618(25)00440-2. [Epub ahead of print]222 108015

Metabolic modulation of CD8⁺ T cells by metformin: A promising adjuvant strategy for CD8⁺ T Cell-Based Immunotherapies.

Quynh Chau Ton Nu, Pil-Hoon Park.

  CD8⁺ T cells play a pivotal role in immune defense through their cytotoxic activity. However, persistent antigen exposure and immunosuppressive microenvironments drive CD8⁺ T cells into a dysfunctional or exhausted state, thereby limiting the effectiveness of CD8⁺ T cell-based immunotherapies. Increasing evidence indicates that CD8+ T cell activation and effector functions are tightly coupled to dynamic metabolic reprogramming that sustains the energetic and biosynthetic requirements for effective immune responses. Metformin, beyond its established role as an antidiabetic medication, demonstrates considerable promise as an immune-metabolic adjuvant capable of enhancing the efficacy of CD8⁺ T cell-based immunotherapies and reshaping immune responses across various pathological conditions. In this review, we provide a comprehensive overview of the current insights into the metabolic and functional regulation of CD8⁺ T cells by metformin in a context-dependent manner, with an emphasis on its therapeutic potential as an immunotherapeutic adjuvant. We also highlight the translational opportunities and challenges associated with the clinical integration of metformin and propose strategies to overcome context-specific barriers to its clinical application.

Keywords:  CD8(+) T cell; Immunotherapy; Metabolic programming; Metformin

DOI:  https://doi.org/10.1016/j.phrs.2025.108015
Aging Cell. 2025 Nov 07. e70257

Defining Microbiota-Derived Metabolite Butyrate as a Senomorphic: Therapeutic Potential in the Age-Related T Cell Senescence.

Nia Paddison Rees, Jessica Conway, Ben Dugan, Sayeda S Amir, Aimee Parker, Simon R Carding, Niharika A Duggal.

  Advancing age is accompanied by an accumulation of senescent T cells that secrete pro-inflammatory senescence-associated secretory phenotype (SASP) molecules. Gut-microbiota-derived signals are increasingly recognised as immunomodulators. In the current study, we demonstrated that ageing and the accumulation of senescent T cells are accompanied by a reduction in microbial-derived short-chain fatty acids (SCFAs). Culturing aged T cells in the presence of butyrate suppresses the induction of a senescence phenotype and inhibits the secretion of pro-inflammatory SASP factors, such as IL6 and IL8. Administration of faecal supernatants from young mice rich in butyrate prevented in vivo accumulation of senescent spleen cells in aged mice. The molecular pathways governing butyrate's senomorphic potential include a reduced expression of DNA damage markers, lower mitochondrial ROS accumulation, and downregulation of mTOR activation, which negatively regulates the transcription factor NFκB. Our findings establish butyrate as a potent senomorphic agent and provide the evidence base for future microbiome restitution intervention trials using butyrate supplements for combating T cell senescence, ultimately reducing inflammation and combating age-related pathologies to extend lifelong health.

Keywords:  T cell; ageing; cellular senescence; inflammation

DOI:  https://doi.org/10.1111/acel.70257
Nat Immunol. 2025 Nov 07.

Role of oxygen sensing and hypoxia-inducible factors in orchestrating innate immune responses.

Jie Ting Low, Youngjun Kim, Mai Matsushita, Ping-Chih Ho.

Oxygen availability and fluctuation are common changes in tissues and organs undergoing infection and damage. While acute hypoxia can rapidly alter immune cell metabolism and activity, chronic hypoxia can induce long-lasting changes in immune responses via oxygen-guided adaptation in signaling cascades and epitranscriptomic programs. These adaptations are orchestrated mainly by oxygen-sensing hydroxylases and oxygen-sensing epigenetic modifiers that regulate downstream hypoxia-inducible factor pathways and epigenetic reprogramming. In this Review, we summarize how acute and chronic hypoxia influence innate immune cell function and metabolism, thereby tailoring immune cell behavior within the tissue microenvironment. We further highlight the dual roles of hypoxia in regulating innate immune cell function in different (patho)physiological contexts and evaluate therapeutic strategies that target oxygen-sensing pathways to restore immune competence and tissue homeostasis.

DOI: https://doi.org/10.1038/s41590-025-02317-1
Immun Ageing. 2025 Nov 05. 22(1): 51

Ascorbic acid attenuates immunosenescence and cognitive decline via MYH9-Mediated CD8⁺ T cell differentiation.

Taotao Mi, Shanshan Yang, Nan Wang, Fengjiao Huo, Meili Zhao, Shuyao Lv, Tingting Su, Shengyu Feng, Hao Wang, Liuling Guo, Jian-Kang Zhu, Hailiang Liu.

   BACKGROUND: Immune function decline (immunosenescence) accelerates systemic aging and adversely impacts cognitive function. Antioxidants may mitigate these effects; however, the role of ascorbic acid (AA), a key antioxidant, in counteracting immunosenescence and enhancing cognition remains inadequately explored.
RESULTS: In this study, AA administration (0.1 mg/g, tail vein, every 2 days for 30 days) significantly improved cognitive function in aged (16-month) C57BL/6 mice, without altering anxiety-like behavior (as assessed in the open field test). This was associated with elevated peripheral blood lymphocytes (T cells, B cells) and CD8⁺ T cells, alongside reduced myeloid cells (CD11b⁺). Single-cell RNA sequencing of PBMCs revealed AA reversed immunosenescent signatures-increasing T/B cell populations and decreasing neutrophils/macrophages-mimicking youthful immune profiles. In vitro, AA skewed hematopoietic stem cell (HSC) differentiation toward CD8⁺ T cells (increasing DN2 stage, suppressing myeloid CD11b⁺ cells) and enhanced splenic CD8⁺ T cell generation. Mechanistically, AA bound MYH9, activating cytoskeletal pathways. MYH9 inhibition (blebbistatin) reduced CD8⁺ T cells and increased CD11b⁺ cells-effects rescued by AA. Crucially, CD8⁺ T cell depletion abolished AA's cognitive benefits, confirming their essential role.
CONCLUSIONS: In summary, AA mitigates immunosenescence and improves cognitive function by targeting MYH9 to regulate CD8⁺ T cell differentiation and function. These findings establish a mechanistic basis for AA as a potential therapeutic agent against age-related immune and cognitive decline.

Keywords:  Ascorbic acid; CD8+ t cells; Cognitive functions; Immunosenescence

DOI:  https://doi.org/10.1186/s12979-025-00538-4
J Nanobiotechnology. 2025 Nov 04. 23(1): 701

Multi-modal single-cell platform for nanoparticle-enhanced time-series metabolic profiles of CD8+ T cell exhaustion in tumor immunosurveillance.

Chenjie Yang, Mingxia Gao, Xiangmin Zhang, Hailong Yu, Chunhui Deng.

  Cytotoxic T cells (CD8+) play a pivotal role in immunosurveillance by identifying and eliminating tumor cells. However, the onset of CD8+ T cell exhaustion, characterized by overexpression of immune checkpoint receptors, impairs their function, allowing tumor cells to evade immunosurveillance. Single-cell metabolic profiles hold the promise in characterizing intrinsic cellular metabolic heterogeneity of exhausted CD8+ T cells, even at ultra-early time points. Herein, we developed a multi-modal single-cell platform that integrates nanoparticles-enhanced laser desorption/ionization mass spectrometry and protein number counting platform to elucidate the temporal dynamics of CD8+ T cell exhaustion. A comprehensive time-series analysis was conducted, with nearly 3000 single cells performing metabolic profile extraction and checkpoint receptors quantification. Our results demonstrated that the onset of exhaustion was as early as 3 h post-stimulation and upon cessation of stimulation, a degree of reversibility was observed in these exhausted cells. Using deep learning algorithms, the discrimination of the different exhausted CD8+ T cell subpopulations from the control achieved an area under the curve value of more than 0.904, even to 1.000 with 100% sensitivity and specificity. Our work presents a robust, high-throughput, and scalable system for multi-modal single-cell analysis, offering valuable insights into the dynamics of CD8+ T cell exhaustion.

Keywords:  CD8+ T cell exhaustion; LDI-MS; Metabolic profiles; Nanoparticles; Single-cell

DOI:  https://doi.org/10.1186/s12951-025-03774-4
Eur J Immunol. 2025 Nov;55(11): e70084

Epigenetically Controlled ZEB2 Expression Promotes the Cytotoxic Potential of CMV-Specific CD8+ T Cells.

Varun Sasidharan Nair, Zheng Yu, Hosein Ahmadi, Agnes Bonifacius, Beate Pietzsch, Dirk H Busch, Luka Cicin-Sain, Fabian Müller, Kilian Schober, Britta Eiz-Vesper, Stefan Floess, Jochen Huehn.

  Zinc finger E-box binding protein 2 (ZEB2) is a key factor in the differentiation of naïve CD8+ T cells into effector and memory T cells. However, the precise regulatory role of ZEB2 in cytotoxic CD8+ T cells remains unknown. Our recent DNA methylation analysis of cytomegalovirus (CMV)-specific human CD8+ T cells revealed two differentially methylated regions (DMRs) within the ZEB2 locus. In the present study, we show that these ZEB2 DMRs undergo pronounced demethylation during T cell differentiation. In particular, terminally differentiated CD8+ T cells and cytotoxic CD4+ T cells show an almost complete demethylation. Demethylation of the ZEB2 DMRs correlates strongly with ZEB2 expression in all T cell subsets. Furthermore, DNA methylation patterns remain stable during long-term in vitro culture. ZEB2 knockout in CD8+ effector T cells results in altered gene expression profiles, affecting genes related to cell-cell adhesion and impairing the cytotoxic capacity in CMV-specific killing assays. Our data show that ZEB2 expression contributes to the differentiation of naïve CD8+ T cells into effector and memory T cells and regulates the functional properties of virus-specific cytotoxic CD8+ T cells.

Keywords:  CD8+ T cells; cell–cell adhesion; cytotoxicity; epigenetics

DOI:  https://doi.org/10.1002/eji.70084
Cancer Res. 2025 Nov 06.

Tumor-Associated Macrophages Produce PGE2 to Promote CD8+ T Cell Exhaustion and Drive Resistance to PD-L1 Blockade in Microsatellite Stable Colorectal Cancer.

Jean-David Fumet, Charlène Latour, Lisa Nuttin, Valentin Derangère, Alis Ilie, Pauline Russo, Léa Hampe, Susy Daumoine, Marion Thibaudin, Caroline Truntzer, Francois Ghiringhelli, Emeric Limagne.

Immune checkpoint blockade treatment is highly effective in microsatellite instable (MSI) colorectal cancer (CRC). However, microsatellite stable (MSS) tumors, are intrinsically resistant to immunotherapy. Here, we sought to better understand the mechanisms of resistance to anti-PD-L1 therapy in CRC by characterizing the immune profiles of MSS and MSI tumor models. While both tumor types presented intratumoral CD8+ T cell and PD-L1 expression, the exhausted CD8+ T cell phenotypes differed. In the MSS tumors, exhausted CD8+ T cells co-expressed PD-1 and TIGIT and exhibited a terminal exhausted profile with low cytokine secretion and limited cytotoxic function. In contrast, PD-1+ CD8+ T cells in MSI tumors did not express TIGIT and displayed higher cytokine and cytotoxic activities. Interestingly, immunosuppressive M2-like tumor-associated macrophages (TAM) accumulated in MSI tumors and positively correlated with PD-1+ TIGIT+ CD8+ T cell frequency. M2-like TAM depletion reduced TIGIT expression, increased CD8+ T cell function, and improved efficacy of PD-L1 blockade. Transcriptomic analysis revealed elevated COX1/2 expression in TAMs in MSS tumors compared to MSI tumors. COX2 and prostaglandin E2 receptor inhibition impeded TIGIT expression and restored CD8+ T cell activity, while PGE2 triggered TIGIT upregulation in CD8+ T cells. Single-cell, spatial, and bulk transcriptomic data from CRC patients substantiated the correlation between elevated TIGIT in CD8+ T cell and COX1/2 in TAMs. Together, these data uncover the role of the TAM axis in inhibiting PD-L1 efficacy in MSS CRC and support the utility of combining anti-PD-L1 therapy with TIGIT blockade, PGE2 treatment, or M2-like TAM inhibition in CRC.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0079
STAR Protoc. 2025 Oct 30. pii: S2666-1667(25)00579-9. [Epub ahead of print]6(4): 104173

Protocol for halofuginone-mediated metabolic reprogramming of murine T cells via activation of the GCN2 pathway.

Meghan Kates, Michael St Paul, Pamela S Ohashi, Samuel D Saibil.

  Modifying T cell metabolism and activating conserved stress pathways can enhance T cell efficacy in adoptive cell therapy for cancer treatment. Here, we present a protocol to activate the General Control Non-depressible 2 (GCN2)-mediated branch of the integrated stress response (ISR) in murine T cells using the drug halofuginone. We outline the process of isolating CD8+ T cells from T cell receptor transgenic mice, activating them with bone-marrow-derived dendritic cells, and subsequently activating GCN2 and the ISR with halofuginone. For complete details on the use and execution of this protocol, please refer to St. Paul et al.1.

Keywords:  Cell Biology; Cell isolation; Immunology; Metabolism

DOI:  https://doi.org/10.1016/j.xpro.2025.104173
Nat Aging. 2025 Nov 05.

A natural compound revitalizes the aging human immune system.

DOI: https://doi.org/10.1038/s43587-025-01012-y
Front Immunol. 2025 ;16 1658015

Mass cytometric analysis of circulating immune landscape in primary central nervous system lymphoma.

Yuchen Wu, Liwei Lv, Jing Liu, Xuefei Sun, Chunji Gao, Shengjun Sun, Nan Ji, Wenjing Wang, Yuanbo Liu.

   Introduction: The peripheral immune profiles of patients with primary central nervous system lymphoma (PCNSL) remain poorly characterized. Investigating immune dysregulation in PCNSL may help elucidate the underlying disease mechanisms.
Methods: We aimed to define the circulating immune landscape in PCNSL by characterizing the immune cell profiles in 16 patients and 6 healthy participants using mass cytometry.
Results: Patients exhibited significant alterations in peripheral blood mononuclear cells, including expansion of CD45RO+ classical monocytes (p=0.017), reduced intermediate subsets (p=0.01), and elevated CD38 expression (p<0.001). The number of terminally differentiated CD8+CD57+ T cells increased (p=0.013), and treatment induced effector T cell (CD8+ T effector/effector memory cells, p<0.05) expansion, accompanied by co-upregulation of CD38, HLA-DR, and CD107a (p<0.01). Patients < 60 years had higher frequencies of CD8+ naïve T cells (p<0.05), and progressive disease correlated with CD56brightNK cell accumulation (p<0.01).
Conclusion: the circulating immune landscape in PCNSL is characterized by skewed monocyte activation, T cell terminal exhaustion, and chemotherapy-induced effector T cell expansion. Our findings link peripheral immune features to the tumor microenvironment biology. Understanding these systemic immune alterations may provide insights into tumor immune evasion and offer a roadmap for reversing PCNSL-associated immunosuppression.

Keywords:  T cell exhaustion; immunosuppression; mass cytometry; primary central nervous system lymphoma (PCNSL); tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1658015
Proc Natl Acad Sci U S A. 2025 Nov 11. 122(45): e2409564122

Drug-loaded bispecific T cell nanoengager overcomes T cell exhaustion for potent cancer immunotherapy.

Jinjin Wang, Xisha Huang, Qiangqiang Shi, Kelsey L Swingle, Alex G Hamilton, Ningqiang Gong, Michael J Mitchell.

  Bispecific T cell engager (BiTE) therapeutics that link T cells and tumor cells to induce tumor cell lysis have demonstrated great success in the clinic for the treatment of many cancers. However, T cell exhaustion in the tumor microenvironment leads to tumor cell escape and BiTE therapy resistance. Herein, we developed a drug-loaded bispecific T cell nanoengager (NanoBiTE) to overcome this obstacle. NanoBiTE is composed of a mesoporous silica nanoparticle encapsulating the adenosine A2A receptor antagonist PBF-509 as a core, with a lipid layer surface coating as a shell and modification with anti-CD19 and anti-CD3 antibodies for tumor and T cell binding, respectively. Like the traditional BiTE blinatumomab, NanoBiTE can engage T cells with CD19+ tumor cells to promote tumor cell lysis. However, unlike blinatumomab, which tends to induce T cell exhaustion, we showed that the release of PBF-509 from NanoBiTE suppressed the A2AR pathway and substantially improved tumor cell killing induced by NanoBiTE. Moreover, NanoBiTE treatment led to substantially reduced tumor burden in vivo in a humanized mouse model. Our results demonstrate that NanoBiTE is a safe and potent bispecific therapy that can also reduce T cell exhaustion for cancer immunotherapy.

Keywords:  T cell; cancer; immunotherapy; nanomedicine

DOI:  https://doi.org/10.1073/pnas.2409564122
Sci Rep. 2025 Nov 06. 15(1): 38897

Proteomic signatures and mitochondrial dysfunctions in peripheral T cells reveal novel ınsights into Alzheimer's disease.

Sebile Koca, Irem Kiris, Sevki Sahin, Sibel Karsidag, Nilgun Cinar, Ahmet Tarik Baykal.

  Alzheimer's disease (AD) exhibits progressive cognitive decline and recent scientific studies hint to the peripheral immune system as a contributor. In this study, we isolated peripheral immune cells including CD4 + and CD8 + T cells, CD14 + monocytes and CD19 + B cells from AD patients and age-matched controls via fluorescence-activated cell sorting. Label-free LC-MS/MS-based proteomic expression analysis within each cell type, comparing AD and control groups independently, 387 significantly altered proteins were identified in CD4 + and 121 in CD8 + T cells. Bioinformatic analysis uncovered distinct, cell-type-specific signatures: CD4 + cells showed dysregulation in ribosomal and RNA-binding proteins linked to neurodegeneration and oxidative stress while CD8 + cells showed elevated glycolytic enzyme expression and hyperpolarized mitochondrial membrane potential. Furthermore, mitochondrial functional assays, JC-1 and MitoSOX Red, further supported cell-type-dependent differences in mitochondrial activity. These findings may suggest that peripheral T cells have unique proteomic and functional alterations in AD, implicating mitochondrial dysfunction as a potential contributor to disease pathology.

Keywords:  Alzheimer’s disease; CD4 + T cell; CD8 + T cell; LC–MS/MS; Mitochondrial membrane potential; Oxidative stress

DOI:  https://doi.org/10.1038/s41598-025-22783-9
Nat Aging. 2025 Nov 04.

Aging represses oncogenic KRAS-driven lung tumorigenesis and alters tumor suppression.

Emily G Shuldiner, Saswati Karmakar, Min K Tsai, Jess D Hebert, Yuning J Tang, Laura Andrejka, Maggie R Robertson, Minwei Wang, Colin R Detrick, Hongchen Cai, Rui Tang, Christian A Kunder, David M Feldser, Dmitri A Petrov, Monte M Winslow.

Most cancers are diagnosed in people over 60 years of age, but little is known about how age impacts tumorigenesis. While aging is accompanied by mutation accumulation (widely understood to contribute to cancer risk) it is associated with numerous other cellular and molecular changes likely to impact tumorigenesis. Moreover, cancer incidence decreases in the oldest part of the population, suggesting that very old age may reduce carcinogenesis. Here we show that aging represses oncogenic KRAS-driven tumor initiation and growth in genetically engineered mouse models of human lung cancer. Moreover, aging dampens the impact of inactivating many tumor suppressor genes with the impact of inactivating PTEN, a negative regulator of the PI3K-AKT pathway, weakened disproportionately. Single-cell transcriptomic analysis revealed that neoplastic cells in aged mice retain age-related transcriptomic changes, showing that the impact of age persists through oncogenic transformation. Furthermore, the consequences of PTEN inactivation were strikingly age-dependent, with PTEN deficiency reducing signatures of aging in cancer cells and the tumor microenvironment. Our findings underscore the interconnectedness of the pathways involved in aging and tumorigenesis and document tumor-suppressive effects of aging that may contribute to the deceleration in cancer incidence with age.

DOI: https://doi.org/10.1038/s43587-025-00986-z
Cell Rep. 2025 Nov 03. pii: S2211-1247(25)01297-5. [Epub ahead of print]44(11): 116526

Cancer-associated adipocytes mediate CD8+T cell dysfunction via FGF21-driven lipolysis.

Sumiya Dalangood, Cegui Hu, Chenwei Yuan, Xiang Li, Wen Qiao, Hanjun Li, Rongyu Zhang, Luying Li, Peng Li, Xiang Yu, Wenjin Yin, Jinsong Lu, Jun Gui.

  Cancer-associated adipocytes (CAAs) reprogram the metabolic status of the tumor microenvironment (TME). The metabolic crosstalk between CAAs and CD8+T cells in the TME remains unclear. Here, we report that CAAs undergo lipolysis, releasing free fatty acids that promote lipid peroxidation and disturb mitochondrial homeostasis in CD8+T cells, leading to their functional exhaustion. Importantly, we uncover that fibroblast growth factor 21 (FGF21) drives CAA lipolysis in an autocrine manner by upregulating adipose triglyceride lipase (ATGL) via FGFR1/KLB-p38 signaling. FGF21 deletion in adipose tissue or ATGL inhibition impedes CAA lipolysis, mitigates lipid peroxidation, normalizes mitochondrial dynamics of CD8+T cells, and restores their effector function, consequently blunting tumor growth. Moreover, FGF21 deficiency or ATGL inhibition enhances the anti-tumor activity of CD8+T cells in response to anti-PD-1 treatment, yielding greater therapeutic efficacy. Our findings highlight the pivotal role of CAA lipolysis in CD8+T cell dysfunction within the TME, suggesting that targeting CAA lipolysis represents a valuable avenue for improving cancer immunotherapy.

Keywords:  ATGL; CD8(+)T; CP: cancer; CP: immunology; FGF21; T cell exhaustion; cancer-associated adipocytes; lipolysis; tumor immunity

DOI:  https://doi.org/10.1016/j.celrep.2025.116526
Nat Commun. 2025 Nov 03. 16(1): 9484

Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function.

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, Marta Williams, Morgan Marsden, Douglas J Veale, Luke C Davies, Micah Niphakis, David K Finlay, Linda V Sinclair, Benjamin F Cravatt, Andrew E Hogan, James A Nathan, Ian R Humphreys, 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.

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 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 murine models 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 in female mice. Collectively, our work provides pre-clinical evidence that ABHD11 is an encouraging drug target in T-cell-mediated inflammation.

DOI: https://doi.org/10.1038/s41467-025-65417-4
Cancer Immunol Immunother. 2025 Nov 03. 74(12): 358

Increased CD103-CD8+ TILs with TPEX phenotype replenish anti-tumor T cell pool in mismatch repair-proficient CRC.

Jinsheng Liu, Jintao Zeng, Ting Zhou, Mi Wu, Xiufang Weng.

  While mismatch repair-deficient (dMMR) colorectal cancers (CRCs) exhibit strong immunogenicity and better response to immune checkpoint inhibitors, the more prevalent mismatch repair-proficient (pMMR) CRCs typically show poor T- cell infiltration and inferior outcomes. Profiling the limited tumor-infiltrating CD8+ T cells helps identify responders and guides new strategies to enhance their infiltration and function in pMMR CRC tumors. Our study reveals that the proportion and number of CD103-CD8+ T (CD103N) cells are significantly increased in pMMR CRC tissue compared to adjacent non-tumor tissue. Distinguish from CD103+CD8+ T (CD103P) cells with elevated TEX markers, these CD103N cells display a precursor exhausted T cells (TPEX) phenotype with elevated stemness properties, reduced exhaustion markers, and retained functional capacity to secrete anti-tumor mediators. Moreover, CD103N cells in pMMR CRC shared a substantial number of identical TCR clonotypes with both CD103P cells in tumor and CD103N cell in peripheral blood. In dMMR CRC patients, enrichment of TPEX-like CD103N cells is associated with a favorable prognosis following anti-PD-1 therapy, suggesting their association with clinical outcome. Our findings identify an expanded population of CD103N cells exhibiting a TPEX phenotype with anti-tumor potential in pMMR CRC, highlighting their promise as therapeutic targets for recruitment into the tumor microenvironment to enhance the efficacy of immunotherapy.

Keywords:  Anti-PD-1treatment; CD103−CD8+ T cells; Colorectal cancer; TCR clonotypes; TPEX phenotype

DOI:  https://doi.org/10.1007/s00262-025-04214-w
Mol Biol Rep. 2025 Nov 01. 53(1): 37

Metabolic reprogramming of immune cells in the battle against intracellular bacterial chronic infections: novel mechanisms and breakthroughs.

Rongrong Jiang, Xiao Liu, Fangtao Xing, Yurong Fu, Zhengjun Yi.

  Chronic intracellular bacterial infections persist within host cells by evading immune clearance, imposing prolonged metabolic stress on the host. In response, the immune system undergoes metabolic reprogramming to sustain prolonged defense. A key feature of this reprogramming is the shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, which enhances pro-inflammatory and antimicrobial responses. Concurrently, fatty acid and amino acid catabolism provide additional metabolic support. Beyond shaping immune function, these metabolic shifts also influence the trajectory of infection by altering the host-pathogen metabolic interplay. In this review, we focus primarily on Mycobacterium tuberculosis (Mtb) infection and integrate quantitative flux analyses of carbon and nitrogen distribution, emphasizing how these metabolic changes connect to epigenetic regulation. We also explore metabolic reprogramming in five representative immune cell types-comprising both innate and adaptive immune cells-to elucidate how their distinct metabolic profiles influence host defense mechanisms and disease progression. Building on these foundations, we propose an innovative metabolic competition model between host and pathogen, offering new insights into the intricate interplay of metabolic networks in chronic intracellular infections.

Keywords:  Immune cells; Infection; Intracellular bacterial; Metabolic reprogramming

DOI:  https://doi.org/10.1007/s11033-025-11218-3
Int J Biol Macromol. 2025 Oct 30. pii: S0141-8130(25)09083-X. [Epub ahead of print]332(Pt 2): 148526

Value of CD8+ T cell-related genes and IL-6/STAT3 signaling pathway in the prognosis of HCC and experimental investigation.

Yuan Wu, Xiaoli Liu, Lihua Yu, Huiwen Yan, Yuqing Xie, Qing Pu, Yuling Liang, Yaxian Kong, Zhiyun Yang.

  CD8+ T cell dysfunction plays a critical role in immune evasion in hepatocellular carcinoma (HCC), yet its regulatory mechanisms remain unclear. In this study, we identified 59 CD8+ T cell-related genes by integrating TCGA transcriptomic data with differential expression and WGCNA analyses. A LASSO-Cox regression model was used to construct a prognostic risk score, which effectively stratified HCC patients into high- and low-risk groups. The high-risk group was enriched in IL-6 receptor binding and JAK-STAT signaling pathways. Functional experiments have shown that overexpression of IL-6 activates the IL-6R/STAT3 axis and promotes T cell exhaustion by up-regulating the expression of the transcription factor c-MAF, leading to an increase in inhibitory receptors (PD-1, TIM-3, TIGIT). IL-6 blockade reversed this phenotype and restored CD8+ T cell function. Clinical sample analysis confirmed elevated p-STAT3 and c-MAF expression in IL-6R+CD8+ T cells, correlating with increased exhaustion. These findings suggest that CD8+ T cell-based risk models may serve as effective prognostic tools in HCC and that targeting the IL-6/STAT3 axis represents a promising immunotherapeutic strategy.

Keywords:  CD8(+) T cells; Hepatocellular carcinoma; IL-6/STAT3; Prognosis

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.148526
Nat Cardiovasc Res. 2025 Nov 06.

Circulating interleukin-18 drives expansion of pathogenic CD57+CD8+ T cells in acute myocarditis.

Elisa Martini.

DOI: https://doi.org/10.1038/s44161-025-00751-w
Immunity. 2025 Nov 03. pii: S1074-7613(25)00434-0. [Epub ahead of print]

Microbiota-derived butyrate promotes a FOXO1-induced stemness program and preserves CD8+ T cell immunity against melanoma.

Annabell Bachem, Michele Clarke, Geraldine Kong, Ilaryia Tarasova, Lachlan Dryburgh, Lindsay Kosack, Ariane R Lee, Lewis D Newland, Teagan Wagner, Emma Bawden, Kah Min Yap, Michael D Wilson, Sven Engel, Kayla R Wilson, Brendan E Russ, Kshitij Tandon, Peter Kar Han Lau, Grant McArthur, Vanessa R Marcelino, Paul A Beavis, Stephen J Turner, Jason Waithman, Timothy P Stinear, Shahneen Sandhu, Jan Schröder, Thomas Gebhardt, Sammy Bedoui.

  A range of microbiota species correlate with improved cancer outcomes in patients and confer protection in pre-clinical mouse models. Here, we examined how microbiota regulate CD8+ T cell immunity against melanoma. Spontaneous control of cutaneous melanoma in mice correlated with metabolic pathways required for microbial synthesis of short-chain fatty acids (SCFAs) shared between several microbiota species. Diet-induced enforcement of SCFA production by the gut microbiota reduced melanoma progression and enriched tumor-specific stem-like CD127+CD8+ T cells in the tumor-draining lymph node (tdLN). The SCFA butyrate induced a FOXO1-driven stemness program and directly promoted the differentiation of tumor-specific CD127+CD8+ T cells in the tdLN. Metabolic flux modeling predicted enhanced microbial production of butyrate in melanoma patients with complete therapeutic responses to immune checkpoint blockade (ICB), and butyrate induced transcriptional features of ICB responsiveness in CD8+ T cells. Our findings suggest a critical role for metabolite production shared across several microbiota species in the preservation of stem-like tumor-specific CD8+ T cells.

Keywords:  CD8 T cells; SCFAs; butyrate; melanoma; metabolism; microbiome; microbiota; stemness

DOI:  https://doi.org/10.1016/j.immuni.2025.10.004
Adv Sci (Weinh). 2025 Nov 03. e15097

Differentiated T Lymphocytes and Cancer Cell Mitochondrial Metabolism to Enhance Radioimmunotherapy by a Biomimetic Nanozyme System.

Hanyu Zhang, Yuhan Deng, Yantong Lu, Miao Wang, Kun Qiao, Zifan Yang, Shipeng Ning, Tong Liu.

  Strategies to enhance the anti-tumor immune response through the regulation of cellular metabolism are under intensive investigation. Herein, a T cell membrane (TCM)-coated biomimetic magnesium carbonate (MgCO3)/Fe-CD hybrid nanozyme system loaded with the Pyruvate kinase M2 (PKM2) activator TEPP-46 (TFMP) is developed, designed to simultaneously induce mitochondrial metabolic reprogramming in both T cells and tumor cells following radiotherapy (RT). The TCM coating enables TFMP to specifically target tumor tissues that highly express PD-L1, where it competitively binds to PD-L1 and thereby alleviates immune checkpoint-mediated T cell suppression. Upon X-ray irradiation, TFMP continuously catalyzes the conversion of radiotherapy-generated hydrogen peroxide into hydroxyl radicals, thereby sustaining reactive oxygen species production, which leads to mitochondrial damage and immunogenic cell death in tumor cells. Moreover, TFMP can neutralize the acidic tumor microenvironment, while the released Mg2+ and TEPP-46 further augment T cell activation and mitochondrial function, thereby increasing the production of ATP and granzyme B, which effectively eliminate residual tumor cells. Experimental results demonstrate that the combination of TFMP and RT can significantly inhibit tumor progression and activate anti-tumor immunotherapy. This TFMP enhances the efficacy of breast cancer radioimmunotherapy, offering a foundation for developing more comprehensive therapeutic approaches of breast cancer to achieve clinical benefits.

Keywords:  PKM2 activator; biomimetic nanozyme; mitochondrial metabolism; radioimmunotherapy; sustaining ROS production

DOI:  https://doi.org/10.1002/advs.202515097
J Transl Med. 2025 Nov 06. 23(1): 1230

Metabolic reprogramming through PIM3 inhibition reverses hypoxia-induced CAR-T cell dysfunction in solid tumors.

Muya Zhou, Luxia Xu, Jinhua Hu, Wenwen Chen, Jialu Hong, Mufeng Wang, Zhigang Guo.

   BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapy has shown remarkable success in hematologic malignancies but faces significant challenges in solid tumors due to the immunosuppressive tumor microenvironment (TME). Among these, hypoxia plays a vital role, yet the molecular mediators that link hypoxia to CAR-T dysfunction remain incompletely understood.
METHODS: Anti-mesothelin (MSLN) CAR-T cells were cultured under normoxic (21% O2) and hypoxic (1% O2) conditions for six days. We assessed cell expansion, phenotypes, cytotoxicity, and metabolic features. RNA sequencing was conducted to identify key gene expression changes induced by hypoxia. Findings were further validated using anti-CD70 CAR-T cells.
RESULTS: Hypoxia reduced CAR-T proliferation, increased apoptosis, lowered memory phenotypes, raised exhaustion, and weakened cytotoxicity in short-term and long-term assays. Transcriptomic and metabolic analyses showed metabolic reprogramming with increased glycolysis and reduced oxidative phosphorylation. Among the dysregulated genes, the serine/threonine-protein kinase PIM3 emerged as a previously underexplored mediator of hypoxia-driven dysfunction. Genetic or pharmacologic inhibition of PIM3 counteracted hypoxia-induced impairment, enhancing memory phenotypes of CAR-T cells, and improving their anti-tumor activity both in vitro and in vivo.
CONCLUSIONS: This work identifies PIM3 as a previously underexplored target that links hypoxia to CAR-T cell dysfunction and demonstrates that PIM3 inhibition can reverse these effects. These findings provide a mechanistic rationale for incorporating PIM3 inhibition into CAR-T cell manufacturing or engineering to improve their therapeutic potential in hypoxic solid tumors.

Keywords:  Chimeric antigen receptor (CAR)-T cell therapy; Hypoxia; PIM3; Solid tumor; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12967-025-07278-5
Science. 2025 Nov 06. eadx9717

NUDT5 regulates purine metabolism and thiopurine sensitivity by interacting with PPAT.

Zheng Wu, Phong T Nguyen, Varun Sondhi, Run-Wen Yao, Zhifang Lu, Tao Dai, Jui-Chung Chiang, Feng Cai, Imani M Williams, Eliot B Blatt, Zengfu Shang, Ling Cai, Jing Zhang, Mya D Moore, Islam Alshamleh, Xiangyi Li, Tamaratare Ogu, Lauren G Zacharias, Rainah Winston, Joao S Patricio, Xandria Johnson, Wei-Min Chen, Qian Cong, Thomas P Mathews, Yuanyuan Zhang, Limei Zhang, Ralph J DeBerardinis.

Cells generate purine nucleotides through de novo purine biosynthesis (DNPB) and purine salvage. Purine salvage represses DNPB to prevent excessive purine nucleotide synthesis through mechanisms that are incompletely understood. We identified Nudix hydrolase 5 (NUDT5) as a DNPB regulator. During purine salvage, NUDT5 suppresses DNPB independently of its catalytic function but through interaction with phosphoribosyl pyrophosphate amidotransferase (PPAT), the rate-limiting enzyme in the DNPB pathway. The NUDT5-PPAT interaction promoted PPAT oligomerization, suppressed PPAT's enzymatic activity, and facilitated disassembly of the purinosome, a metabolon that functions in DNPB. Disrupting the NUDT5-PPAT interaction overcame DNPB suppression during purine salvage, permitting excessive DNPB and inducing thiopurine resistance. Therefore, NUDT5 governs the balance between DNPB and salvage to maintain appropriate cellular purine nucleotide concentrations.

DOI: https://doi.org/10.1126/science.adx9717
J Immunol Res. 2025 ;2025 7550012

Spermidine Remodels the Mitochondrial Metabolism of Tumor-Infiltrating Lymphocytes.

Yizhe Sun, Hao Fu, Xinyu Li, Meng Wan, Hongchao Xiong, Chaoting Zhang.

  Adoptive cell therapy (ACT) utilizing tumor-infiltrating lymphocytes (TILs) has significant potential in treating various cancers; however, its effectiveness is often compromised by the tendency of TILs to become exhausted and dysfunctional. Revitalizing these essential immune cells is crucial for amplifying their antitumor efficacy. Our study investigates the influence of spermidine on the metabolic pathways of TILs, focusing on its critical contribution to T cell vitality. We assessed the impact of spermidine on glucose absorption, mitochondrial functionality, and energy production in TILs. The application of spermidine resulted in a pronounced improvement in mitochondrial functionality and energy production, indicated by a surge in mitochondrial numbers and enhanced activity of the tricarboxylic acid (TCA) cycle. Importantly, the suppression of mitochondrial metabolism negated the beneficial effects of spermidine on mitigating exhaustion and enhancing cellular activity, highlighting the essential role of mitochondrial metabolism in the action of spermidine. Our research suggests that modulation of metabolism by spermidine could be a potential strategy to strengthen the antitumor capabilities of TIL-based treatments, offering a promising method to better manage solid tumors.

Keywords:  TCA cycle; metabolism; mitochondria; spermidine

DOI:  https://doi.org/10.1155/jimr/7550012