bims-imseme 2025-12-07 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2025–12–07
twenty-two papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Metabolic reprogramming of CAR T cells: a new frontier in cancer immunotherapy.
Cytochrome c oxidase dependent respiration is essential for T cell activation, proliferation and memory formation.
Metabolic-immune nexus in tumor microenvironment: From mechanistic insights to therapeutic opportunities.
CD8+ T cell stemness precedes post-intervention control of HIV viremia.
T cell priming by high avidity neoantigens in lymph nodes augments adoptive immunotherapy.
ETV1 Drives CD4+ T Cell-Mediated Intestinal Inflammation in Inflammatory Bowel Disease Through Amino Acid Transporter Slc7a5.
Oxidative pentose phosphate pathway is required for T cell activation and antitumor immunity.
Cluster-derived, tumour-reactive T cells from clinical samples.
Stem-like CD8+ T cells preserve HBV-specific responses in HBV/HIV co-infection.
Buoyant mass reveals distinct T cell states predictive of checkpoint response.
Metabolic regulation of T cell production of IL-10 and IL-22 protects against intestinal inflammation.
Protein restriction reshapes aging across organs.
Propagation of monocyte exhaustion memory and underlying mechanisms.
Age-related immune states and PD-1 blockade: mechanisms and strategies for the elderly.
Loss of B3GAT1/HNK-1 disrupts glioma-CD8+ T cell immune synapse formation for immune escape.
CD8+ T cells drive myofibroblast activation and contraction via JAK/STAT3 and TGFβ signaling.
T-regulatory cell protection of progenitor cells from CD4 + T-cell-mediated cytotoxicity is essential for endogenous mouse digit-tip regeneration.
Beyond the genome: epigenetic regulation of immune responses and T cells in brain tumors.
Interleukin-2 Surface Displayed M1 Macrophage-Derived Extracellular Vesicles for Modulating the Tumor Microenvironment.
SYK regulates Schwann cell metabolic reprogramming to promote axonal regeneration in immune-mediated neuropathy.
CD74+CCL5+ effector CD8+ T cells drive mucosal inflammation and predict biologics response in inflammatory bowel disease.
Dietary Polyunsaturated Fatty Acids Regulate Dendritic Cell Function via Nrf2-dependent Control of Ferroptosis.

Front Immunol. 2025 ;16 1688995

Metabolic reprogramming of CAR T cells: a new frontier in cancer immunotherapy.

Tjaša Frlic, Mojca Pavlin.

  Chimeric Antigen Receptor (CAR) T cell therapy has revolutionized hematological cancer treatment, but its efficacy in solid tumors remains limited by the immunosuppressive and metabolically hostile tumor microenvironment (TME). CAR T cells' functional compromise, exhaustion, and poor persistence are critically linked to their suboptimal metabolic fitness. This review highlights a paradigm shift: immunometabolism and its intricate interplay with epigenetics profoundly regulate T cell fate and function, establishing their reprogramming as a cornerstone for optimizing CAR T cell efficacy in diverse malignancies. We explore the intricate relationship between T cell differentiation and metabolic states, emphasizing that modulating CAR T cell metabolism ex vivo during manufacturing can drive differentiation towards less exhausted, more persistent memory phenotypes, such as stem cell central memory (Tscm) and central memory (Tcm) cells, which correlate with superior anti-tumor responses. Our analysis demonstrates that metabolic inhibitors offer significant potential to reprogram CAR T cells. Agents targeting glycolysis or the PI3K/Akt/mTOR pathway promote a memory-like phenotype by favoring oxidative phosphorylation (OXPHOS). Further strategies utilizing glutamine antagonists, mitochondrial modulators, or enzyme manipulation (e.g., IDH2, ACAT1) can epigenetically reprogram cells, fostering memory and exhaustion resistance. Similarly, nutrient level optimization during ex vivo expansion directly sculpts CAR T cell metabolic profiles. With approaches like glucose restriction/galactose substitution, or specific amino acid modulation (e.g., L-arginine, asparagine), persistence of CAR T cells in patients can be improved. The judicious selection and engineering of cytokines (e.g., IL-7, IL-15, IL-21) during manufacturing also plays a vital role in fostering desired memory phenotypes. In conclusion, metabolic engineering, leveraging its impact on epigenetic regulation during CAR T cell manufacturing, is crucial for generating potent, persistent, and functionally resilient products. This approach holds immense promise for expanding the curative potential of CAR T cell therapy to a broader range of cancers, particularly challenging solid tumors.

Keywords:  T cell differentiation; adoptive cell immunotherapy; chimeric antigen receptor (CAR); epigenetics; exhaustion; immunometabolism; metabolic modulation; persistence

DOI:  https://doi.org/10.3389/fimmu.2025.1688995
Nat Commun. 2025 Dec 04. 16(1): 10898

Cytochrome c oxidase dependent respiration is essential for T cell activation, proliferation and memory formation.

Tatiana N Tarasenko, Emily Warren, Bharati Singh, Amanda Fuchs, Jose Marin, Marten Szibor, Christopher King, Peter J McGuire.

T cell activation requires extensive metabolic reprogramming, but the specific requirement for mitochondrial respiration (MR) remains unresolved. While most studies have focused on aerobic glycolysis as the primary driver of proliferation and effector function, the role of MR has not been completely defined. To isolate MR from proton pumping by cytochrome c oxidase (COX), we expressed the non-proton-pumping alternative oxidase (AOX) in activated COX-deficient T cells. AOX restored electron flow, membrane potential, and mitochondrial ATP production, ultimately rescuing proliferation, effector and memory differentiation, and antiviral immunity. These improvements required upstream electron input, particularly from Complex I, with Complex II and DHODH contributing more modestly. Despite restored MR, glycolysis remained elevated, likely due to altered redox signaling. These findings demonstrate that MR, normally mediated by COX, is necessary and can be sufficient to support T cell activation and function, independent of proton translocation, provided upstream electron input is maintained.

DOI: https://doi.org/10.1038/s41467-025-65910-w
Chin Med J (Engl). 2025 Dec 01.

Metabolic-immune nexus in tumor microenvironment: From mechanistic insights to therapeutic opportunities.

Wenjie Zhu, Yingchen Chu, Peng Gao.

   ABSTRACT: The metabolic-immune interplay within the tumor microenvironment (TME) is a critical determinant of tumor progression and immune evasion, presenting significant therapeutic opportunities for enhancing antitumor immunity. The TME is characterized by hypoxia, acidosis, and nutrient depletion, and is also profoundly shaped by the metabolic reprogramming of cancer cells, including enhanced glycolysis, as well as amino acid and lipid metabolism. These metabolic alterations establish an immunosuppressive niche, restricting nutrient availability for effector T cells while enriching the environment with metabolites such as lactate, kynurenine, and adenosine. These metabolites impair the function of cytotoxic T lymphocytes and natural killer cells, while also promoting the survival and activity of regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells. Immune cell function within this challenging milieu is dictated by metabolic adaptability: Effector T cells succumb to metabolic exhaustion, whereas regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells exhibit metabolic flexibility that sustains their survival and suppressive functions. Therapeutic strategies that target cancer cell metabolism or enhance the metabolic fitness of immune cells offer promising approaches to mitigating immunosuppression within the TME. Notably, combining metabolic modulators with existing immunotherapies holds great potential for amplifying antitumor responses. Nonetheless, critical hurdles for clinical translation remain, including target specificity, potential toxicities, and adaptive metabolic plasticity. Further investigation into metabolic reprogramming and precision immunotherapy, guided by emerging biomarkers, is critical for optimizing therapeutic efficacy and improving patient outcomes by fully leveraging the metabolic-immune axis.

Keywords:  Immunotherapy resistance; Metabolic reprogramming; Metabolic–immune nexus; Therapeutic targeting; Tumor microenvironment

DOI:  https://doi.org/10.1097/CM9.0000000000003908
Nature. 2025 Dec 01.

CD8+ T cell stemness precedes post-intervention control of HIV viremia.

Zahra Kiani, Jonathan M Urbach, Hannah Wisner, Mpho J Olatotse, Daniel Y Chang, Joshua A Acklin, Alicja Piechocka-Trocha, Nathalie Bonheur, Ashok Khatri, Mathias Lichterfeld, Jesper D Gunst, Ole S Søgaard, Marina Caskey, Michel C Nussenzweig, Bruce D Walker, David R Collins.

Interventions to induce lasting HIV remission are needed to obviate the requirement for lifelong antiretroviral therapy (ART). Durable post-intervention control (PIC) of viremia has been achieved in a subset of individuals following broadly neutralizing anti-HIV-1 antibody (bNAb) administration and analytical treatment interruption (ATI)1-4. Prior studies support a role for CD8+ T cells5-9 but the precise features of CD8+ T cells involved in PIC remain unclear. Here we mapped and functionally profiled CD8+ T cell responses to autologous HIV epitopes using longitudinal samples from four ATI trials in bNAb recipients. PIC was associated with superior pre-intervention HIV-specific CD8+ T cell proliferative capacity, stem cell-like memory phenotype, and recall cytotoxicity against autologous HIV peptide-pulsed CD4+ T cells. CD8+ T cell stemness was further increased following bNAb administration without emergence of new clonotypes targeting defined HLA-optimal epitopes. Multimodal single-cell analyses revealed molecular features associated with PIC and HIV-specific CD8+ T cell stemness, including signatures of metabolic fitness and reduced T cell exhaustion. These results identify immune features that precede subsequent PIC to inform the development of combination immunotherapies that will elicit durable HIV remission.

DOI: https://doi.org/10.1038/s41586-025-09932-w
Cancer Immunol Res. 2025 Dec 05.

T cell priming by high avidity neoantigens in lymph nodes augments adoptive immunotherapy.

Megen C Wittling, Amalia M Rivera Reyes, Megan M Wyatt, Anna C Cole, Aubrey S Smith, Guillermo O Rangel Rivera, James H Carmouche, Kailey G Diatikar, Ayana T Ruffin, Michael B Ware, Frances J Bennett, Connor J Dwyer, Riley M F Pihl, Soundharya Kumaresan, Gregory B Lesinski, Chrystal M Paulos, Hannah M Knochelmann.

Adoptive transfer of T lymphocytes specific for tumor-associated neoantigens can elicit immunity against solid tumors in patients. However, how these antigens impact T cell function, effector differentiation, and persistence remains unclear. We examined how an identical CD8+ T cell product was shaped by melanoma expressing either a low-avidity tumor-associated antigen or high-avidity neoantigen, and kinetically profiled T cell differentiation in these two contexts across host tissues. High-avidity neoantigen expression was sufficient to activate naïve CD8+ T cells - leading to robust tumor regression and long-term protective immunity upon tumor rechallenge. Mechanistically, transferred naïve CD8+ T cells reacting to high-avidity neoantigen exhibited enhanced cytokine production, heightened effector function, and sustained persistence compared to the low-avidity wild-type tumors. Antitumor activity to these high-avidity tumors was preserved even in the absence of functional host T and B lymphocytes, and early lymph node trafficking was found to be essential for ACT efficacy. Expanded effector or stem-memory T cells were compared to the naïve pmel-1 T cell product. Stem-memory but not effector-memory cells exhibited similar antitumor efficacy and lymph node trafficking patterns to the naïve cells in mice with high-avidity neoantigen tumors. These findings highlight how differential tumor antigens shape divergent cellular fate and uncover a critical role of T cell trafficking in lymph nodes in shaping high-avidity neoantigen-specific antitumor responses.

DOI: https://doi.org/10.1158/2326-6066.CIR-25-0514
Adv Sci (Weinh). 2025 Dec 05. e11595

ETV1 Drives CD4+ T Cell-Mediated Intestinal Inflammation in Inflammatory Bowel Disease Through Amino Acid Transporter Slc7a5.

Yan Shi, Song Wang, Yuqing Yan, Wei Chen, Yingying Cao, Dafan Chen, Wei Chen, Caiyun Ma, Xinjian Wan.

  Excessive CD4+ T cell responses drive inflammatory bowel disease (IBD), yet the transcriptional mechanisms underlying their dysfunction remain incompletely understood. Here, it is demonstrated that E-twenty-six variant transcription factor 1 (ETV1) is upregulated in IBD patients and positively correlates with disease severity. Etv1 deficiency impairs CD4+ T cell activation, proliferation, and T helper 17 (Th17) cell differentiation, thereby ameliorating TNBS-induced colitis. Moreover, Etv1 deficiency attenuates CD45RBhighCD4+ T cell-induced colitis, characterized by a reduction in pathogenic CD4+ T cells in the intestinal mucosa. Pharmacological inhibition of ETV1 ameliorates colitis in recombination activating gene 1-deficient mice and suppresses human IBD T cell responses ex vivo. Mechanistically, Etv1 binds to the promoter of the gene encoding the amino acid transporter solute carrier family 7 member 5 (Slc7a5), enhancing its expression and subsequent amino acid uptake to fuel T cell pathogenicity. Restoring Slc7a5 expression rescues the proliferation, differentiation, and colitogenic function of Etv1-deficient CD4⁺ T cells. Clinically, SLC7A5 is upregulated in IBD, and its blockade ameliorates T cell-driven colitis in vivo. Collectively, the results establish a critical role for the ETV1-Slc7a5 axis in driving pathogenic CD4⁺ T cell responses in IBD, highlighting this pathway as a novel therapeutic target.

Keywords:  ETV1; SLC7A5; Th17; inflammatory bowel diseases

DOI:  https://doi.org/10.1002/advs.202511595
Proc Natl Acad Sci U S A. 2025 Dec 09. 122(49): e2516288122

Oxidative pentose phosphate pathway is required for T cell activation and antitumor immunity.

Zihong Chen, Kellen L Olszewski, Rolf-Peter Ryseck, Xincheng Xu, Jacob A Boyer, Christian G Peace, Yihui Shen, Caroline R Bartman, Lydia Lynch, Joshua D Rabinowitz.

  Glucose is catabolized by two major metabolic pathways, glycolysis and the oxidative pentose phosphate pathway (oxPPP). The oxPPP generates nicotinamide adenine dinucleotide phosphate (NADPH) at two steps, glucose-6-phosphate dehydrogenase (G6PD), the most common enzyme deficiency in humans, and 6-phosphogluconate dehydrogenase (PGD). Previous literature suggests that G6PD supports but PGD limits T cell-mediated immunity. Here, we use T cell-specific knockout mouse models to show that both enzymes are required for antitumor immunity and response to immunotherapy. PGD knockout depletes mature T cells systemically, while G6PD loss does not reduce basal T cell populations but results in apoptosis upon activation. Such apoptosis is not reversed by major downstream products of the oxPPP, including antioxidants, nucleosides, or fatty acids. Instead, T cells are partially rescued by removal of media cystine, whose reduction requires NADPH. G6PD loss induces an oxidative stress response that upregulates cystine import, which together with low NADPH leads to fatal disulfide stress. Overall, these results highlight an essential role for the oxidative pentose phosphate pathway in cystine homeostasis and T cell-mediated immunity.

Keywords:  NADPH; T cell activation; T cell antitumor immunity; disulfide stress; oxidative pentose phosphate pathway

DOI:  https://doi.org/10.1073/pnas.2516288122
Nat Rev Immunol. 2025 Dec 02.

Cluster-derived, tumour-reactive T cells from clinical samples.

Kirsty Minton.

DOI: https://doi.org/10.1038/s41577-025-01256-0
Gut. 2025 Dec 04. pii: gutjnl-2025-335461. [Epub ahead of print]

Stem-like CD8+ T cells preserve HBV-specific responses in HBV/HIV co-infection.

Anucha Preechanukul, Aljawharah Alrubayyi, Bo Sun, Edward Arbe-Barnes, Jonida Kokici, Frances Gorou, Sarun Prasitdumrong, Kelly A S da Costa, Natasha Fisher-Pearson, Noshin Hussain, Stephanie Kucykowicz, Indrajit Ghosh, Fiona Burns, Sabine Kinloch, Pedro Simoes, Sanjay Bhagani, Patrick T F Kennedy, Mala K Maini, Rachael Bashford-Rogers, Upkar S Gill, Dimitra Peppa.

   BACKGROUND: Chronic hepatitis B virus (HBV) infection disproportionately affects people living with HIV, who are often excluded from functional cure studies.
OBJECTIVE: This study investigates CD8+ T cell profiles in HBV mono-infection versus HBV/HIV co-infection, examining the impact of long-term therapy on virus-specific responses to inform therapeutic strategies for immune restoration.
DESIGN: We analysed CD8+ T cell responses in 61 participants (HBV n=20, HBV/HIV n=20, HIV n=21), on suppressive antiviral therapy, assessing transcriptomic and proteomic profiles, focusing on exhaustion markers alongside virus-specific functional capabilities.
RESULTS: Transcriptomic analysis revealed distinct signatures in co-infection, with upregulation of TCR signalling genes, inhibitory pathways and progenitor-exhausted markers (XCL2, TCF7, PDCD1, IL7R). This profile scored highly for a precursor exhausted (Tpex) CD8+ T cell signature, reflecting stemness that maintains plasticity despite chronic antigen exposure. Proteomic analysis confirmed higher frequencies of Tpex (TCF-1+CD127+PD-1+) CD8+ T cells in co-infection, while HBV mono-infection showed predominance of terminally exhausted ToxhighTCF-1-CD127- cells. Tpex enrichment extended to HBV-specific populations corresponding with more robust, polyfunctional HBV-specific responses in co-infection against surface and core antigens. HBV-specific CD8 T cells maintained enhanced proliferative capacity and checkpoint responsiveness to anti-PDL1 blockade compared with HBV mono-infection. While co-infection was characterised by lower HBsAg levels and longer treatment duration, these factors alone did not account for the distinct immunological profiles.
CONCLUSIONS: People with well-controlled HBV/HIV co-infection maintain robust CD8+ T cell responses with preserved stem-like properties supporting antiviral function. These results challenge assumptions about additive immune dysfunction in dual chronic infections and highlight the need for tailored immune-modulatory therapies.

Keywords:  CELLULAR IMMUNITY; CHRONIC VIRAL HEPATITIS; HEPATITIS B; IMMUNE RESPONSE; IMMUNOLOGY

DOI:  https://doi.org/10.1136/gutjnl-2025-335461
bioRxiv. 2025 Nov 20. pii: 2024.09.26.615179. [Epub ahead of print]

Buoyant mass reveals distinct T cell states predictive of checkpoint response.

Jiaquan Yu, Ye Zhang, Sarah M Duquette, Robert J Kimmerling, James C Kostas, Krystal K Lum, Rachel LaBella, Selim Olcum, Madeleine Vacha, Steve Wasserman, Reginald Aikins, Katie Katsis, Thomas R Usherwood, Sonia Cohen, Teresa Dinter, Aleigha Lawless, Tatyana Sharova, Mark Stevens, Gianfranco L Yee, Weida Wu, Stefani Spranger, Teemu P Miettinen, Ileana M Cristea, Genevieve M Boland, Scott R Manalis.

T cells are central to immune defense, yet existing molecular and phenotypic assays do not fully capture a cell's intrinsic immune potential. Here we show that a single physical property, buoyant mass, reveals hidden heterogeneity within phenotypically similar, resting CD8 + T cells. Using suspended microchannel resonator measurements, we identify two distinct populations: "light" cells, enriched for mitochondrial content but prone to delayed activation and exhaustion, and "heavy" cells, biosynthetically poised for proliferation and memory formation. In patients with melanoma receiving immune checkpoint blockade, pre-treatment buoyant mass profiling of circulating T cells predicted therapeutic response with an accuracy comparable with standard tumor-derived biomarkers. Our findings establish buoyant mass as a label-free, stimulation-independent measure of systemic T cell fitness, providing a rapid and broadly applicable framework for immune profiling and response prediction in cancer and beyond.

DOI: https://doi.org/10.1101/2024.09.26.615179
Precis Clin Med. 2025 Dec;8(4): pbaf025

Metabolic regulation of T cell production of IL-10 and IL-22 protects against intestinal inflammation.

Han Liu, Xiaojing Zhao, Tianming Yu, Yu Yu, Suxia Yao, Wenjing Yang, Yingzi Cong.

   Objectives: Inflammatory bowel disease is driven by dysregulated CD4⁺ T cell responses to the intestinal microbiota. While T cells can exacerbate inflammation by producing proinflammatory cytokines, they also produce anti-inflammatory mediators, such as interleukin 10 (IL-10) and IL-22. However, the metabolic programs that regulate IL-10 and IL-22 production remain incompletely defined.
Methods: We used CBir1 transgenic mice and in vitro Th1 polarization assays to investigate how metabolic pathways regulate T cell production of IL-10 and IL-22. A panel of metabolic inhibitors was tested for their effects on cytokine expression. Transcriptional mechanisms were assessed using bulk RNA sequencing, qPCR, Enzyme-linked immunosorbent (ELISA), and CRISPR-Cas9-mediated gene editing. Functional relevance was validated using Citrobacter rodentium infection and T cell suppression assays in vivo and in vitro.
Results: Among tested metabolic inhibitors, dichloroacetate (DCA) significantly enhanced IL-10 and IL-22 production by CD4⁺ T cells. DCA increased maximal oxygen consumption and decreased lactate secretion in T cells. Mechanistically, DCA upregulated aryl hydrocarbon receptor (Ahr) and downregulated Bhlhe40, without affecting Prdm1. Pharmacologic inhibition of Ahr suppressed DCA-induced IL-22, but not IL-10, while Bhlhe40 knockout enhanced IL-10 production, identifying distinct transcriptional regulators for each cytokine. Functionally, DCA-treated Th1 cells suppressed naïve T cell proliferation via IL-10. In an in vivo experiment, DCA treatment protected mice from C. rodentium-induced colitis.
Conclusions: Our findings demonstrate that DCA enhances IL-22 and IL-10 production in Th1 cells through Ahr and Bhlhe40, respectively. These results identify a novel metabolic mechanism by which DCA promotes mucosal immune regulation and highlight its potential as a therapeutic strategy for inflammatory bowel disease.

Keywords:  Ahr; Bhlhe40; IL-10; IL-22; T cell metabolism; dichloroacetate

DOI:  https://doi.org/10.1093/pcmedi/pbaf025
Nat Aging. 2025 Dec 03.

Protein restriction reshapes aging across organs.

Qingzhong Ren.

DOI: https://doi.org/10.1038/s43587-025-01043-5
Cell Commun Signal. 2025 Dec 05.

Propagation of monocyte exhaustion memory and underlying mechanisms.

Jing Wang, Blake A Caldwell, Yajun Wu, Babak Razani, Liwu Li.

  Monocyte exhaustion is a dysfunctional state characterized by prolonged pathogenic inflammation and immune suppression, commonly observed in chronic infections and sepsis. However, the mechanisms underlying the generation and propagation of exhausted monocytes remain poorly understood. In this study, we investigate the impacts of exhausted monocytes on neighboring naïve monocytes, endothelial cells, and T cell function. Using an in vitro co-culture system, we demonstrate that exhausted monocytes induced by prolonged LPS stimulation propagate the exhaustion phenotype to neighboring naïve monocytes. Meanwhile these exhausted monocytes can promote endothelial apoptosis, upregulate adhesion molecules ICAM-1 and VCAM-1, and enhance monocyte transmigration, contributing to endothelial dysfunction. Pharmacological inhibition of CD38, a key marker of monocyte exhaustion, significantly mitigates these effects, highlighting its critical role in monocyte-driven endothelial alterations. Furthermore, we show that exhausted monocytes suppress T cell proliferation and activation, a process reversed by CD38 inhibition. We also identify mTOR signaling as a key regulator of monocyte exhaustion and its propagation, with mTOR inhibition partially restoring monocyte functionality by downregulating exhaustion markers and STAT1/STAT3/S6K signaling. Collectively, our findings highlight the CD38-mTOR axis as a central driver of monocyte exhaustion and its pathological consequences, offering potential therapeutic targets for reversing immune dysfunction in inflammatory diseases.

Keywords:  CD38; Exhaustion; Monocyte memory dynamics; Propagation; Sepsis

DOI:  https://doi.org/10.1186/s12964-025-02536-x
J Immunother Cancer. 2025 Dec 01. pii: e013783. [Epub ahead of print]13(12):

Age-related immune states and PD-1 blockade: mechanisms and strategies for the elderly.

Tomonori Yaguchi, Kenji Chamoto, Tasuku Honjo.

  Aging impairs antitumor immunity and may reduce the efficacy of immune checkpoint inhibitors (ICIs). However, the underlying mechanisms remain unclear. Building on our recent findings, we review three key mechanisms of CD8+ T-cell aging: elevated T-cell receptor (TCR) activation thresholds, mitochondrial dysfunction, and disruption of proteostasis. Studies in aged mice have revealed that aged naïve T cells exhibit defective priming due to increased CD45 expression, which raises the TCR activation threshold and restricts effector differentiation. Aging also impairs mitochondrial metabolism, particularly fatty acid oxidation. Furthermore, we highlight the role of proteostasis collapse, including defective autophagy and increased endoplasmic reticulum stress, as a contributor to T-cell dysfunction. Spermidine, a polyamine that declines with age, has the potential to modulate both mitochondrial function and proteostasis. Its supplementation has been shown to improve programmed cell death-1 blockade responsiveness in aged mice. Although clinical studies in humans have yielded inconsistent results regarding the effect of chronological age on ICI efficacy, identifying patients with "age-related" immune microenvironments may enable stratified therapeutic approaches based on insights from preclinical aging models.

Keywords:  Immune Checkpoint Inhibitor; Mitochondria; T cell; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2025-013783
Int Immunopharmacol. 2025 Dec 02. pii: S1567-5769(25)01865-X. [Epub ahead of print]169 115877

Loss of B3GAT1/HNK-1 disrupts glioma-CD8+ T cell immune synapse formation for immune escape.

Jin Duan, Yilin Lin, Zewei He, Melitta Schachner, Stanley L Lin.

  Glioma is an immunologically evasive tumor with a lymphocyte-deficient tumor immune landscape, suggesting an unknown failure in tumor-stroma interaction. The human natural killer-1 glycan (HNK-1) is present on neurons and immune cells, suggesting a potential source of glioma-stroma interaction, cross-talk, and immune regulation. Immunohistochemical staining of a human glioma microarray showed that HNK-1 progressively decreased with increasing tumor grade. However, similar immunohistochemical staining for β-1,3-glucuronic acid transferase (B3GAT1), the predominant enzyme responsible for HNK-1 synthesis, showed no change with glioma progression, indicating that the loss of HNK-1 was not due to changes in B3GAT1 expression. However, Kaplan-Meier analysis showed that B3GAT1 levels positively correlated with survival. In the syngeneic GL261 murine glioblastoma model, HNK-1 knockdown by two B3gat1 shRNAs accelerated glioma growth and reduced mouse survival in vivo. B3gat1-knockdown tumors had increased numbers of regulatory T cells, and decreased numbers of effector CD8+ T cells, which correlated with increased CD8+ T-cell apoptosis. In co-cultures of CD8+ T cells with B3gat1-knockdown GL261 cells, we observed reduced T-cell-induced glioma Ca2+ signaling and intracellular perforin accumulation, along with increased perforin release into the culture medium, compared to CD8+ T-cell co-culture with wild-type GL261 cells. FACS analysis showed loss of co-stimulatory CD80, an immune synapse component, following B3gat1 knockdown. These results suggest that loss of HNK-1 expression contributes to tumor immune escape through loss of immune recognition and attack via downregulation of tumor cell surface co-stimulatory molecules, leading to reduced CD8+ T-cell activation and immune synapse formation, and increased T-cell apoptosis.

Keywords:  Anti-MAG neuropathy; Autoimmunity; HNK-1; Immunological synapse; T cells; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.intimp.2025.115877
iScience. 2025 Dec 19. 28(12): 113904

CD8+ T cells drive myofibroblast activation and contraction via JAK/STAT3 and TGFβ signaling.

Theodoros Ioannis Papadimitriou, Anne van Essen, Merel Willemse, Daphne Dorst, Elly Vitters, Birgitte Walgreen, Hans J P M Koenen, Peter van der Kraan, Marije Koenders, Rogier M Thurlings, Arjan van Caam.

  Fibrosis in rheumatic connective tissue diseases is marked by CD8+ T cell and pro-fibrotic myofibroblast infiltration, though the role of CD8+ T cells in myofibroblast activity remains unexplored. To address this, we developed a 3D cell culture model of immunity-driven fibrosis by combining the classic mixed lymphocyte reaction and a 3D myofibroblast contractility model. Upon co-culture with myofibroblasts, CD8+ T cells more strongly induced myofibroblast contraction and activation than CD4+ T cells. This was not associated with cytotoxicity but with increased IL-6 production by CD8+ T cells and pSTAT3 and TGFβ signaling in myofibroblasts. Use of the JAK/STAT3-inhibitor tofacitinib or the TGFβ receptor inhibitor SB-505124 inhibited the activated myofibroblast phenotype, and combined use of both inhibitors had a clear additive effect. Our findings reveal a previously underappreciated non-canonical role of CD8+ T cells in fibrosis, providing new light to the mechanisms of the human immune system.

Keywords:  Fibrosis; Immunology

DOI:  https://doi.org/10.1016/j.isci.2025.113904
bioRxiv. 2025 Nov 19. pii: 2025.11.19.689270. [Epub ahead of print]

T-regulatory cell protection of progenitor cells from CD4 + T-cell-mediated cytotoxicity is essential for endogenous mouse digit-tip regeneration.

Zachery Beal, Robyn E Reeve, Elizabeth Hammond, Nadia Rosenthal, James Godwin.

Regeneration of amputated digit tips in humans and mice relies on osteoclast-dependent bone erosion coupled with osteoblast-mediated bone replacement. Currently, little is known of the impact of lymphoid immune cells, i.e., T cells, B cells, and NK cells, on digit-tip regeneration. Using lymphoid-deficient mutant mice, we revealed lymphoid immunity as a net negative regulator of regeneration. CD8 + cells are thought to negatively regulate fracture repair; however, we showed that adoptive cell transfer (ACT) of CD8 + T cells into lymphoid-deficient hosts did not impact regeneration. In contrast, ACT of CD4 + T cells potently inhibited regeneration via osteoclast and osteoblast progenitor-cell cytotoxicity. CD4 + T-cell-mediated inhibition of regeneration was rescued by supplementation with T regulatory cells or recombinant RANKL, a mediator of osteoclast differentiation. ACT of IFN-γ-deficient CD4 + T cells abolished cytotoxic activity and rescued regeneration. Future strategies protecting endogenous progenitor cells could enhance human tissue repair and autologous stem-cell therapies.
One sentence summary: Endogenous progenitor cells are vulnerable to CD4 + T-cell-mediated cytotoxicity during digit-tip regeneration and require T-regulatory-cell-mediated protection from autoimmune attack.
Highlights: Digit-tip regeneration is enhanced with the loss of lymphoid immunity.Regeneration requires T regulatory cells (T-regs) for maintenance of osteoclastogenesis when other lymphoid cells are present.T-regs enhance regeneration in the absence of lymphoid immunity during the anabolic phase. Like thymic NK cells, CD4 + T cells and not CD8 + T cells are responsible for inhibition of regeneration. RANKL is essential to the rate-limiting catabolic phase of digit-tip regeneration. Both T-regs and recombinant RANKL can rescue CD4 + T-cell inhibition. Genetic knockout of key cytotoxicity genes (IFNγ, Prf1, and TNFα) in immune-competent mice enhances regeneration. CD4 + T-cell ACT induces both apoptosis and necroptosis. CD4 + T-cell cytotoxicity is dependent on IFNγ.

DOI: https://doi.org/10.1101/2025.11.19.689270
Front Immunol. 2025 ;16 1690552

Beyond the genome: epigenetic regulation of immune responses and T cells in brain tumors.

Shuo Sun, Yu Han, Haiying Li, Chengyan Wang, Shu Zhou, Xiaowei Zhang, Shuhong Dai, Yao Peng, Zhuoqun Wang.

  Brain tumors such as glioblastoma remain among the most lethal and immunologically resistant cancers, in large part due to epigenetic programs that sculpt the tumor-immune microenvironment. DNA methylation, histone modifications, and chromatin remodeling do not merely drive tumor-intrinsic changes; they also profoundly reprogram immune responses, shaping antigen presentation, cytokine signaling, and immune cell recruitment. At the center of this regulation are T cells, whose effector functions are suppressed through promoter hypermethylation of antigen-processing genes, silencing of interferon pathways, and the establishment of exhaustion-specific chromatin states. Mutations such as IDH1/2 and H3K27M further reinforce these epigenetic barriers, fostering immune-cold microenvironments that disable cytotoxic T-cell activity. Emerging evidence highlights both CNS-specific adaptations, including microglial and astrocytic epigenetic programs that reinforce immune privilege, and conserved features of T cell exhaustion that mirror those in peripheral cancers. This duality underscores the need for therapeutic strategies that dismantle CNS-specific barriers while leveraging shared exhaustion programs across tumor types. Epigenetic drugs, ranging from DNA methyltransferase and EZH2 inhibitors to BET degraders and CRISPR-based epigenome editors, are beginning to restore antigenicity, reverse T cell dysfunction, and sensitize tumors to checkpoint blockade. Yet these approaches carry the paradoxical risk of disrupting CNS immune tolerance, potentially triggering harmful neuroinflammation or autoimmunity. To our knowledge, this is among the first comprehensive reviews to integrate CNS-specific immune privilege mechanisms with peripheral exhaustion pathways, providing a unified perspective on how epigenetic regulation orchestrates immune dysfunction across central and peripheral contexts. By mapping the continuum between immune evasion and global immunosuppression, we propose a conceptual framework for tailoring epigenetic-immunotherapy combinations to achieve durable antitumor immunity in the CNS.

Keywords:  T cells; brain tumors; epigenetics; glioblastoma; immunotherapy; tumor immune microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1690552
Int J Nanomedicine. 2025 ;20 14185-14200

Interleukin-2 Surface Displayed M1 Macrophage-Derived Extracellular Vesicles for Modulating the Tumor Microenvironment.

Kyeong Tae Kim, Jeong Hyun Lee, Su Jin Kang, Won Jong Rhee.

   Purpose: Cancer immunotherapy aims to enhance the immune system's ability to recognize and eliminate cancer cells, providing a sustained and effective immune response. However, the tumor microenvironment (TME), characterized by an abundance of tumor-associated M2 macrophages and the presence of exhausted or naïve T cells (non-effector T cells), remains a major barrier to effective immunotherapy. Herein, inflammatory M1 macrophage-derived extracellular vesicles (M1EV) were surface-modified to display interleukin-2 (M1EV_IL2), aiming to develop a multifunctional cancer immunotherapeutic agent capable of modulating both innate and adaptive immune responses.
Methods: We engineered M1EV to label the surface with azide groups through metabolic glycoengineering and developed M1EV_IL2 that displayed IL-2 via bioorthogonal chemistry. M1EV_IL2 were purified by size-exclusion chromatography (SEC) and characterized through comprehensive analyses, including nanoparticle tracking analysis (NTA). In vitro macrophage repolarization and T cell activation were evaluated at the gene-expression level, followed by ex vivo assays assessing T-cell proliferation, cytokine secretion, and activation marker expression.
Results: M1EV_IL2 effectively retained the intrinsic physicochemical properties of EVs while displaying IL-2 stably on its surface. It upregulated M1 macrophage markers, IL-1β and CXCL10, while downregulating the M2 macrophage marker CD206, thereby inducing M2-to-M1 macrophage repolarization. In addition, M1EV_IL2 also activated CD4+ T cells and induced the activation of naïve CD8+ T cells to effector T cells, leading to enhanced cell proliferation and secretion of antitumor cytokines.
Conclusion: These results indicate that M1EV_IL2 has the potential to reshape the tumor immune landscape by simultaneously activating macrophages and T cells, thereby enhancing both innate and adaptive immune responses. Unlike conventional cancer therapies, which directly target tumor cells, M1EV_IL2 is expected to enhance immune responses, potentially mitigating adverse effects while improving therapeutic efficacy.

Keywords:  T cell activation; cancer immunotherapy; extracellular vesicles; interleukin-2; macrophage repolarization

DOI:  https://doi.org/10.2147/IJN.S546777
J Neuroinflammation. 2025 Dec 06.

SYK regulates Schwann cell metabolic reprogramming to promote axonal regeneration in immune-mediated neuropathy.

Nannan Zhang, Chen Liu, Fangyu Chen, Qian Zheng, Yuzhong Wang, Fangzhen Shan.

  Immune-mediated peripheral neuropathies like acute motor axonal neuropathy (AMAN) drive axonal degeneration through unresolved neuroinflammation, where Schwann cell (SC) metabolic reprogramming fails to support regeneration. While Spleen Tyrosine Kinase (SYK) is recognized for orchestrating immune responses and central glial function, its role in SC immunometabolism remains unknown. We identify SYK as a master regulator bridging neuroinflammation and SC metabolic adaptation in AMAN. SYK was compensatorily upregulated in SCs at sciatic nerve lesions following anti-GD1a IgG-mediated autoimmune injury, suggesting its activation is part of the protective response. Experimental SYK deficiency triggered catastrophic metabolic collapse, impairing glycolysis and oxidative phosphorylation via dysregulated PI3K/AKT/mTOR and HIF-1α/c-Myc signaling. This suppressed glucose uptake, glycolytic enzymes, mitochondrial biogenesis, and electron transport chains, exacerbating mitochondrial damage. Crucially, loss of this SYK response disrupted AMPK/STAT3-dependent mitophagy, causing ROS accumulation and mitochondria-dependent apoptosis, linking metabolic failure to glial degeneration. SYK deficiency further impaired neuro-glial metabolic coupling, reducing lactate production and MCT1-mediated transfer to axons, which compromised axonal bioenergetics. In vivo, targeted SYK knockdown in AMAN mice to block this endogenous upregulation amplified neuroinflammation, impaired nerve bioenergetics, exacerbated muscle atrophy, and worsened neurofunctional deficits. Mechanistically, SYK integrates immune-triggered metabolic reprogramming with mitochondrial quality control to fuel regeneration. These findings establish SYK as a pivotal upstream coordinator of SC metabolism and neuro-immunomodulation that enables metabolic support for axonal regeneration. Targeting SYK to enhance its activity represents a promising metabolic therapy for immune-mediated neuropathy.

Keywords:  Energy metabolism; Mitophagy; Peripheral nerve regeneration; Schwann cell; Spleen tyrosine kinase

DOI:  https://doi.org/10.1186/s12974-025-03624-y
J Transl Med. 2025 Nov 29.

CD74+CCL5+ effector CD8+ T cells drive mucosal inflammation and predict biologics response in inflammatory bowel disease.

Shanshan Wu, Shuangchun Liu, Caixia Zhang, Bingqing Yu, Jiaxiong Tan, Xiongxiu Liu.

   BACKGROUND: Inflammatory bowel disease (IBD) exhibits heterogeneous mucosal inflammation and variable responses to biologics therapy. This study aimed to identify the immune cell subsets and molecular programs driving disease pathogenesis and to develop predictive biomarkers for therapeutic outcomes.
METHODS: We integrated single-cell RNA sequencing, bulk transcriptomic deconvolution, GWAS-based Mendelian randomization, and gut microbiome profiling across multiple IBD cohorts. Immune-microbial interactions were systematically characterized and linked with clinical phenotypes and treatment response. Immunohistochemistry was performed on colonic tissues from 12 IBD patients and 10 healthy controls to validate CCL5 and CD8 + T cell expression. Flow cytometric analysis of peripheral blood samples from 7 IBD patients and 12 healthy individuals was conducted to assess circulating CCL5 + CD8 + T cell proportions.
RESULTS: CCL5 + effector CD8 + T cells emerged as key mediators of colonic inflammation, displaying high IFN-γ/TNF activity and RUNX3/NF-κB-coordinated transcriptional programs. Immunohistochemical validation demonstrated profoundly elevated CCL5 expression (median 4.170% vs. 0.3450%, P < 0.0001) and CD8 + T cell infiltration (median 2.025% vs. 0.2150%, P < 0.0001) in IBD colonic tissues. Peripheral blood showed modest trends toward increased CCL5 + CD8 + T cells, though far less pronounced than tissue changes. Tissue-resident effector CD8 + T cell abundance correlated with disease severity and infliximab resistance. Six causally associated genes (DMAJCI, RMF167, SPRY1, ZFP96, FKBP11, SELPLG) formed a predictive signature for diagnosis and treatment response. Microbiome analyses revealed disrupted networks and immune-microbiome coupling.
CONCLUSION: CCL5 + CD8 + T cells are profoundly enriched in IBD colonic tissues and drive mucosal inflammation through pro-inflammatory pathways. A six-gene model, particularly involving FKBP11, demonstrated potential for disease stratification and infliximab response prediction. These findings highlight immune and microbial features of IBD that merit further functional and clinical validation.

Keywords:  Biomarkers; Effector CD8+ t cells; Gut microbiome; Inflammation; Inflammatory bowel disease; Mendelian randomization; Single cell RNA sequencing

DOI:  https://doi.org/10.1186/s12967-025-07509-9
Res Sq. 2025 Nov 19. pii: rs.3.rs-7983397. [Epub ahead of print]

Dietary Polyunsaturated Fatty Acids Regulate Dendritic Cell Function via Nrf2-dependent Control of Ferroptosis.

Juan Cubillos-Ruiz, Deepika Awasthi, Erin McMinn, Camilla Salvagno, Sung-Min Hwang, Tito Sandoval, Chang-Suk Chae, Wiam Madani, Jacqueline Crater, Kaushik Sen, Daniel Min, Alexander Emmanuelli, Chen Tan, Andrew Dannenberg, Diana Morales, Evelyn Cantillo, Eloise Chapman-Davis, William Zhang, Suzanne Cloonan.

Dendritic cells (DCs) orchestrate adaptive immune responses to pathogens and tumors, yet how dietary lipids influence DC metabolism and function remains largely unexplored. Here we show that dietary polyunsaturated fatty acids (PUFAs) govern DC activity via Nuclear factor erythroid 2-like 2 (Nrf2)-dependent control of ferroptosis. In mice, an n-6 PUFA-enriched diet suppressed DC Nrf2 signaling, depleted glutathione, and induced lipid peroxidation and ferroptosis, thereby compromising antigen presentation. By contrast, dietary n-3 PUFAs enhanced Nrf2 signaling and redox homeostasis, preserving DC integrity and T cell priming. Pharmacologic Nrf2 activation or ferroptosis inhibition restored the function of DCs from n-6 PUFA-fed mice. Notably, adoptive immunotherapy with DCs conditioned by a diet rich in n-3 PUFAs-but not n-6 PUFAs-elicited durable, T cell-dependent control of metastatic ovarian cancer. These findings identify dietary PUFAs as key modulators of the Nrf2-glutathione-ferroptosis axis in DCs and reveal a redox-sensitive metabolic checkpoint that can be leveraged to improve cancer immunotherapy.

DOI: https://doi.org/10.21203/rs.3.rs-7983397/v1