bims-imseme 2026-02-15 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2026–02–15
thirty-two papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Distinct control of T cell proliferation and effector function by partitioning of intracellular sulfur from cysteine.
CD147 regulates CD8+ T cell cytotoxic activity by facilitating phosphorylation and subsequent recruitment of proximal TCR signaling kinases.
Suppression of CD4 T cells by Tregs dictates metabolic remodeling of CD8 T cells during effector to memory transition.
Reversible control of T cell exhaustion by NR4A transcription factors revealed through targeted protein degradation.
Precision CRISPR annotation of the functional enhancer landscape in primary human T cells.
SPECIFIC: A systematic framework for engineering cell state-responsive synthetic promoters reveals key regulators of T cell exhaustion.
Yin Yang 1-Dependent PcG Function is Essential for TET2 Expression and Early T cell Development.
Diverse Microbial Exposure Enhances CD8 + T Cell Effector Memory Output and Function.
Altered senescence and mitochondrial transcriptome defines age-related changes in satellite cells.
Age-related thymic involution: Mechanistic insights and rejuvenating approaches to restore immune function.
Lipid oxidation reprogramming in cancer-associated fibroblasts enhances CD8+ T cell cytotoxicity and therapeutic response.
Hormonal rewiring of immunity during dietary restriction ensures host defense and systemic glucose conservation.
STING synergizes with TOX suppressing HO-1 expression to trigger ferroptosis in tumor-infiltrating CD8+ T cell and immunotherapy resistance.
Securinine bolsters anti-tumor immunity by promoting CD8⁺ T cell activation.
FASN-mediated metabolic reprogramming drives CD4+ T cell hyperactivation in Sjögren's syndrome via fatty acid oxidation-dependent oxidative phosphorylation.
Leveraging T cells for cancer immunotherapy.
YY1-Mediated Polycomb Group Function Safeguards Hematopoietic Stem Cells from Premature Aging.
Querying functional drivers in primary murine naïve and memory T cells using RNP-mediated CRISPR-Cas9 Gene Deletion.
CAR Signaling Informs Mechanisms to Enhance Metabolism and Function in γδ T Cells.
Engineering "physically optimized" T cells for increased sampling of complex tumor microenvironments.
CXCR6 signaling as a key mediator of CD8+ T cell-driven ICI myocarditis.
SLAMF6 as a drug-targetable suppressor of T cell immunity against cancer.
SAICAR Drives T Regulatory Cell Differentiation and FOXP3 Maintenance to Promote Immunotherapy Resistance.
ALDH1L1 reverses CD8+ T cell exhaustion in the oral squamous cell carcinoma microenvironment by reprogramming L-glutamate metabolism.
C-terminus CD28 phosphorylation (Y218) modulates IL-2 secretion and antitumor effect of CAR-T cells.
The ageing immune system as a driver of systemic ageing.
Interleukin-6 restricts pre-thymic T cell lineage commitment of progenitors driving loss of SIV control.
Flt3L-mediated tumor cDC1 expansion enhances immunotherapy by priming stem-like CD8+ T cells in lymph nodes.
Single-Cell Multiomics Decoding of TCIRG1-Mediated Cuproptosis Circuitry Rewiring Immune-Metabolic Landscape in Ischemic Stroke.
Metabolic crosstalk among cancer-associated fibroblasts, adipocytes and immune cells as an immunosuppressive tumor microenvironment driver.
Transcriptional and epigenetic control of human naïve CD8+ T cell activation.
Substrate availability and citrate alter TCA cycle metabolism and SLC13A3 in macrophage immune responses.

bioRxiv. 2026 Jan 29. pii: 2026.01.27.702014. [Epub ahead of print]

Distinct control of T cell proliferation and effector function by partitioning of intracellular sulfur from cysteine.

Beth Kelly, Minsun Cha, Tatjana Gremelspacher, Jacob L Martin, Massimo Andreis, Gustavo E Carrizo, Mia Gidley, Michal A Stanczak, Petya Apostolova, David E Sanin, Ananya Majumdar, Erika L Pearce.

Delineating how acquired nutrients are partitioned into different intracellular pathways, and how these various fates support distinct functions in T cells is limited. We show that CD8 + T cells acquire cysteine to serve both as a substrate for glutathione (GSH) production, which modulates effector functions, and to cede its sulfur for NFS1-dependent FeS-cluster synthesis, which supports proliferation. NFS1 deletion in activated CD8 + T cells promotes exhaustion and dampens anti-cancer immunity, while blocking cysteine flux into GSH, or enforcing FeS metabolism, enhance tumor control. This role for disrupted FeS metabolism in T cell exhaustion is echoed in data from human HCC. Elucidating how different intracellular pathways use cysteine enables targeted control of cysteine flux to retain beneficial effects of cysteine while abolishing those that restrain function. We illustrate this concept for one metabolite, cysteine, but it is likely to apply to other metabolites relevant for immune cell function.

DOI: https://doi.org/10.64898/2026.01.27.702014
iScience. 2026 Feb 20. 29(2): 114739

CD147 regulates CD8+ T cell cytotoxic activity by facilitating phosphorylation and subsequent recruitment of proximal TCR signaling kinases.

Taiyu Shu, Dan Wang, Hao Wang, Jie Zou, Heyao Qin, Xue Liang, Hongyong Cui, Qian He, Yuxi Zhang, Jianli Jiang.

  CD8+ T cells are the primary cytotoxic cells within the tumor microenvironment, where T cell receptor (TCR) signaling drives their activation and effector functions. However, aberrant TCR activation in this setting often leads to T cell dysfunction. Previous studies suggest that CD147 modulates T cell activation, effector function, and exhaustion. However, the underlying mechanisms remain unclear. Using a CD8+ T cell-specific CD147 knockout model, we showed that CD147 loss significantly enhanced T cell cytotoxicity and reduced exhaustion. Mechanistically, CD147 promoted T cell exhaustion by disrupting proximal TCR kinase signaling through direct interactions with CD3ε, CD3ζ, and LCK, thereby promoting immune escape. Pharmacological inhibition with dasatinib attenuated CD147-driven overactivation and exhaustion. Furthermore, embedding the CD147 intracellular domain into CAR-T constructs significantly enhanced their cytotoxic efficacy while reducing exhaustion. These findings advance our understanding of T cell exhaustion in tumors and may inform strategies to optimize CAR-T therapy.

Keywords:  microenvironment

DOI:  https://doi.org/10.1016/j.isci.2026.114739
bioRxiv. 2026 Feb 03. pii: 2026.02.01.703100. [Epub ahead of print]

Suppression of CD4 T cells by Tregs dictates metabolic remodeling of CD8 T cells during effector to memory transition.

Adithya K Vegaraju, Vandana Kalia, Surojit Sarkar.

Metabolic transitions between naïve, effector and memory T cell states are largely orchestrated by TCR, costimulatory and cytokine signals along with nutrient availability in the immune microenvironment. Treg cells have been shown to play a critical role in the effector-to-memory (E-M) transition of virus-specific CD8 T cells through regulation of proliferation and cytotoxic functional programs. However, the precise Treg-dependent metabolic changes that occur in the microniches and, the underlying molecular and cellular mediators of E-M transition remain undefined. Here we show that Treg cells promote the metabolic remodeling of memory-precursor effector CD8 T cells (MPEC) from aerobic glycolysis to fatty acid oxidation as they enter quiescence after antigen clearance. Our data implicate the anatomic microniche of the splenic white pulp as a site for Treg-MPEC interactions. We further show that optimal E-M metabolic transition requires regulation of effector CD4 T cells and inflammatory myeloid cells through inhibitory CTLA4 signals from Treg cells. Moreover, antagonism of inflammatory cytokine interferon-γ (IFN-γ) signals partially rescues the memory defects associated with absence of Treg cells. Together, these findings support a metabolic triad model of memory CD8 T cell differentiation where Treg-dependent regulation of inflammation from effector CD4 T cells promotes the transition of CD8 T cells from cytotoxic effector to quiescent memory metabolic programs. These studies define novel molecular targets that may be exploited to manipulate metabolism, migration and memory function during vaccination.

DOI: https://doi.org/10.64898/2026.02.01.703100
bioRxiv. 2026 Feb 04. pii: 2026.02.02.701413. [Epub ahead of print]

Reversible control of T cell exhaustion by NR4A transcription factors revealed through targeted protein degradation.

Erik Ehinger, Kristy C Perez, Emi Sanchez, Bruno Villalobos Reveles, Barsha Dash, Leo Josue Arteaga-Vazquez, Eric Johnson, Anjana Rao, Patrick G Hogan.

Tumor-infiltrating CD8 + T cells (TILs) show progressive loss of effector function and upregulation of inhibitory receptors. NR4A transcription factors have emerged as key regulators of this dysfunctional state. Here we developed degron-based systems enabling rapid degradation of endogenous NR4A proteins in both mouse and primary human T cells. We demonstrate that the continuous presence of each NR4A protein is required to maintain suppression of effector cytokines and expression of co-inhibitory receptors; degradation of individual NR4A proteins rapidly restored these functional features, with each NR4A protein exerting prominent effects on distinct as well as overlapping subsets of genes and surface markers associated with effector, memory and exhaustion programs. Transcriptional profiling of phenotypically defined populations revealed both shared and unique gene programs across NR4A family members. Through CRISPR-mediated endogenous gene editing in primary human CD8 + T cells, we show that targeted degradation of NR4A proteins with a small molecule degrader can maintain cytokine expression and suppress inhibitory receptor expression in cells subjected to chronic stimulation, providing a framework for a powerful strategy for therapeutic intervention.
One Sentence Summary: Targeted degradation of endogenous NR4A proteins reveals that individual family members maintain features of T cell dysfunction through overlapping as well as non-redundant mechanisms, providing a therapeutic strategy to restore anti-tumor function.

DOI: https://doi.org/10.64898/2026.02.02.701413
bioRxiv. 2026 Jan 29. pii: 2026.01.27.702006. [Epub ahead of print]

Precision CRISPR annotation of the functional enhancer landscape in primary human T cells.

Ping Wang, Josephine R Giles, Hua Huang, Sasikanth Manne, Martha S Jordan, Alexander C Huang, Junwei Shi, E John Wherry.

Precise modulation of T cell function through engineering the non-coding genome holds great promise for advancing next-generation immunotherapies. However, robust high-throughput approaches to annotate functional cis-regulatory elements (CRE) in human T cells remain limited. Here, we developed a simple and highly efficient CRISPR interference (CRISPRi) perturbation platform to systematically annotate CREs in human primary T cells. Using this platform, we identified novel CREs controlling PDCD1 , HAVCR2 , and TBX21 expression. Combinatorial CRE perturbations revealed synergistic CRE pairs that fine-tune PDCD1 and HAVCR2 expression, while Cas9-indel-based mutagenesis pinpointed the critical nucleotides within each enhancer that are essential for their activity. Functional experiments demonstrated that CRE-edited HAVCR2 outperformed conventional total gene knockout in enhancing CAR T cell anti-tumor efficacy. Moreover, CRE editing of PDCD1 and HAVCR2 repressed PD-1 and TIM-3 expression in human tumor-infiltrating lymphocyte CD8 T cells, highlighting regulatory role of these CREs in disease relevant exhausted T cells. Together, this approach offers a compact CRISPRi platform that enables high-throughput dissection of functionally relevant non-coding genomic regions in T cells, providing insights for mechanistic studies and precision genome engineering of advanced cellular therapies.

DOI: https://doi.org/10.64898/2026.01.27.702006
Quant Biol. 2025 Jun;13(2): e97

SPECIFIC: A systematic framework for engineering cell state-responsive synthetic promoters reveals key regulators of T cell exhaustion.

Zhaoyu Zhang, Xiaoyu Qiu, Hui Ning, Zihua Huang, Minzhen Tao, Min Liang, Zhen Xie.

  Cell state-specific synthetic promoters are essential tools for studying and manipulating cellular function, yet their design remains challenging, particularly for complex states such as T cell exhaustion. Here we present SPECIFIC (Synthetic Promoter Engineering for Cellular State Identification and Functional Analysis), an integrated framework that leverages chromatin accessibility profiling and machine learning to systematically identify and validate cell state-specific synthetic promoters. By comparing exhausted T cells from both mouse OT-I and human CAR-T models, we identified 56 conserved transcription factor binding motifs associated with T cell exhaustion. From these motifs, we engineered a subset of the most promising candidates into synthetic promoters driving an exhaustion-responsive gene circuit that senses and responds to T cell dysfunction. Several synthetic promoters, particularly those containing NFATc2 or MEF2C binding sites, demonstrated remarkable specificity in recognizing the exhausted state and effectively attenuated T cell dysfunction by reducing both CAR expression and exhaustion markers. This study establishes a generalizable approach for designing cell state-specific regulatory elements and provides new strategies for improving CAR-T cell therapy through programmed control of gene expression.

Keywords:  T cell exhaustion; promoter; synthetic biology; synthetic promoter

DOI:  https://doi.org/10.1002/qub2.97
bioRxiv. 2026 Jan 30. pii: 2026.01.27.701530. [Epub ahead of print]

Yin Yang 1-Dependent PcG Function is Essential for TET2 Expression and Early T cell Development.

Yinghua Wang, Sahitya Saka, Xuan Pan.

Yin Yang 1 (YY1) is a multifunctional transcription factor and mammalian Polycomb Group (PcG) protein critical for lymphocyte development. While YY1 is essential for early T-cell development and survival, the underlying epigenetic mechanisms by which YY1 regulates early T-cell development are not fully understood. Herein, we utilized the YY1 PcG function conditional knockout mouse model ( Yy1 -/ΔREPO ) by CRISPR/Cas9 to further dissect the underlying mechanisms. Yy1 -/ΔREPO mice show early T cell development blockage at the double-negative (DN) 3 to single positive T cell transition with expansion of the DN3 population. Yy1 -/ΔREPO DN3 cells are highly proliferative, but more prone to apoptosis, leading to reduced single positive T cells output. The genetic network governing T cell differentiation is deregulated in Yy1 -/ΔREPO DN3 T cells. The YY1 REPO deletion leads to downregulation of DNA demethylase enzyme Tet1 and Tet2 expressions in DN3 cells with no change of Tet3 . Pharmacologic inhibition of TET catalytic activity blocked DN-to-DP progression at the DN3 stage, whereas re-expression of TET2 catalytic domain in Yy1 -/ΔREPO DN thymocytes partially rescued T cell differentiation. Together, our study demonstrates that YY1-mediated PcG function is essential for the DN3 to SP T cell transition and YY1-TET2 axis promotes proper DN3 differentiation.

DOI: https://doi.org/10.64898/2026.01.27.701530
bioRxiv. 2026 Feb 04. pii: 2026.02.02.703037. [Epub ahead of print]

Diverse Microbial Exposure Enhances CD8 + T Cell Effector Memory Output and Function.

immgenT Project

Mice with normalized microbial exposure (NME) harbor an immune system that more accurately reflects that of humans compared to mice maintained as specific pathogen-free (SPF). An explanation for the observed alterations in the composition of the T cell compartment in NME mice has not been reported. We compared the T cell landscape in NME versus SPF mice at baseline and after acute LCMV infection. Using the immgenT dataset, we found no unique T cell populations in NME, but the landscape shifted towards activated T cells with increased propensity for effector functions and improved pathogen clearance. CD8 + KLRG1 + cells (immgenT CD8_cl12) are significantly expanded in NME mice. Their predominance was a result of both increased formation and the conversion of other memory populations to a KLRG1+ phenotype. Thus, NME mice provide insight into a diverse T cell compartment rich with cells previously found to be limited in SPF mice.

DOI: https://doi.org/10.64898/2026.02.02.703037
Front Cell Dev Biol. 2025 ;13 1699206

Altered senescence and mitochondrial transcriptome defines age-related changes in satellite cells.

Fasih A Rahman, Joe Quadrilatero.

  Aging impairs the regenerative capacity of skeletal muscle in part through the functional decline of the resident stem cell population called satellite cells. With age, satellite cells exhibit a loss of quiescence, altered proliferation, and impaired differentiation, leading to incomplete myogenesis following injury. Mitochondria are central to stem cell function, providing ATP, regulating redox homeostasis, and integrating several signaling pathways during lineage progression. While mitochondrial remodeling and function is essential for supporting the metabolic demands of myogenesis, the extent to which these processes are altered in aged satellite cells across cell states remains unclear. To address this, we performed a comparative transcriptomic analysis of young and aged satellite cells in quiescent, proliferating, and early differentiating states using three publicly available microarray datasets. Our results reveal that aged satellite cells exhibit a dysregulated senescence profile, characterized by the simultaneous upregulation of both senescence-inducing and -inhibiting genes, suggestive of a metastable senescence state. These features persisted during early differentiation, where aged cells also displayed increased expression of senescence-associated secretory phenotype (SASP) components, potentially contributing to a pro-inflammatory niche. Mitochondrial gene expression was relatively stable in quiescent cells but showed marked remodeling upon activation, particularly in aged cells. While young satellite cells upregulated transcriptional programs related to mitochondrial function, aged cells exhibited broader and less coordinated responses enriched for stress, apoptotic, and metabolic pathways. Despite evidence of mitochondrial stress, mitophagy gene activation remained limited in aged cells, raising the possibility of impaired organelle quality control. Together, our findings highlight age-associated disruptions in both senescence and mitochondrial remodeling programs across the satellite cell lifecycle. These transcriptional changes likely underlie impaired regenerative responses in aging muscle and identify potential targets for rejuvenating muscle stem cell function.

Keywords:  SASP; aging; mitochondrial remodeling; satellite cell; senescence; skeletal muscle; skeletal muscle regeneration

DOI:  https://doi.org/10.3389/fcell.2025.1699206
Sci Adv. 2026 Feb 13. 12(7): eaeb2970

Age-related thymic involution: Mechanistic insights and rejuvenating approaches to restore immune function.

Jérémy C Santamaria, Magali Irla.

The gradual decline in thymic function with age, known as age-related thymic involution, leads to reduced T cell production, thereby increasing the risk of infections and cancer susceptibility and leading to poor vaccine responses. Moreover, T cell defects were recently involved in the age-related loss of tissue integrity and function. Mechanistically, thymic involution is driven by several factors, including hormonal modifications and chronic inflammation, leading to functional changes in the hematopoietic and stromal compartments. These progressive changes alter the cross-talk between developing T cells and thymic epithelial cells, which is pivotal for thymic function. Promising strategies to counteract thymic involution and rejuvenate immune T cell function have been recently identified. This review summarizes key insights into the underlying mechanisms of thymic involution and discusses current and emerging rejuvenation strategies to restore thymic function. These interventions show promise in regenerative medicine to promote healthy aging by alleviating age-associated immune decline.

DOI: https://doi.org/10.1126/sciadv.aeb2970
Cancer Cell. 2026 Feb 12. pii: S1535-6108(26)00051-6. [Epub ahead of print]

Lipid oxidation reprogramming in cancer-associated fibroblasts enhances CD8+ T cell cytotoxicity and therapeutic response.

Zikun Ma, Yuzhao Wang, Weikai Wang, Wanyang Sun, Rong Wang, Xue Ding, Zibin Chen, Xiangdong Li, Zhiyong Li, Yunlin Ye, Yize Mao, Jianhua Yin, Guibo Li, Rong-Rong He, Xiaoyu Liang, Zhuowei Liu.

  Cancer-associated fibroblasts (CAFs) are major stromal components of the tumor microenvironment, yet how their metabolic states shift during therapy and influence anti-tumor immunity remains unclear. By integrating clinical cancer samples, single-cell RNA analyses, and functional studies, we identify a chemotherapy-conditioned PTGER3+ CAF subset characterized by enhanced lipid oxidation. This metabolic reprogramming strengthens antitumor immunity by promoting CD8+ T cell activation and cytotoxicity through the suppression of PTEN-related signaling. Clinically, higher proportions of therapy-induced PTGER3+ CAFs correlate with improved treatment responses and better patient prognosis. Together, these findings reveal a previously unrecognized stromal metabolic adaptation that supports CD8+ T cell immunity and highlight CAF-driven lipid oxidation and its regulation of CD8+ T cell PTEN signaling as potential avenues to enhance chemotherapy and immunotherapy efficacy.

Keywords:  CD8(+) T cell anti-tumor immunity; PI3K/AKT/mTOR; PTEN; bladder cancer; cancer-associated fibroblasts; cell metabolism; chemotherapy; immunotherapy; lipid metabolism; tumor immune microenvironment

DOI:  https://doi.org/10.1016/j.ccell.2026.01.012
Immunity. 2026 Feb 10. pii: S1074-7613(26)00002-6. [Epub ahead of print]

Hormonal rewiring of immunity during dietary restriction ensures host defense and systemic glucose conservation.

Luisa Menezes-Silva, Mingeum Jeong, Charles Carr, Riley M Schneider, Silvia Pires, Ana C Codo, Jazib Uddin, Alexander Grier, Randy S Longman, Niels Olsen Saraiva Camara, David Artis, Seong-Ji Han, Nicholas Collins.

  Food shortages and infectious diseases were constant threats throughout mammalian evolution and often occurred simultaneously. When food availability is reduced, it is unclear how the host adapts to support glucose-demanding immune processes while preventing hypoglycemia. In the context of dietary restriction (DR), we found that glucocorticoids (GCs) aligned naive, effector, and memory T cell populations with the nutritional status of the host. DR-induced GCs promoted naive T cell homing to the bone marrow, which supported their homeostasis at steady state. Following a primary infection, DR-induced GCs rewired immunity to simultaneously uphold pathogen control and systemic glucose homeostasis. GCs achieved this by dampening effector T cells and enhancing the response of neutrophils with reduced glucose dependence. Although the total effector T cell pool was decreased during DR, GCs enriched memory-precursor effector cells to preserve memory formation. Thus, GCs align immunity and metabolic physiology to ensure host fitness when food availability is reduced.

Keywords:  T cell; caloric restriction; glucocorticoids; hormones; metabolism; neutrophil; nutrition

DOI:  https://doi.org/10.1016/j.immuni.2026.01.003
Nat Commun. 2026 Feb 09.

STING synergizes with TOX suppressing HO-1 expression to trigger ferroptosis in tumor-infiltrating CD8+ T cell and immunotherapy resistance.

Qian Zhu, Jun-Bao Zhang, Cai-Ping Nie, Xiu-Feng Liu, Liang-Ping Zhan, Ming Li, Xi-Liang Zeng, Jia He, He Huang, Xiao-Jun Xia, Song Gao, Xiao-Shi Zhang, Jiang Li.

CD8+ T cell abundance within the tumor microenvironment is a critical determinant of immunotherapy efficacy. Here we show that CD8⁺ T cells lacking STING or TOX display markedly improved antitumor activity, with enhanced tumor infiltration and elevated IFN-γ and granzyme B production. These STING or TOX deficient cells exhibit a stem-like transcriptional state and resist ferroptosis by suppressing lipid peroxidation pathways while promoting mitochondrial biogenesis. Mechanistically, STING and TOX form a positive regulatory loop that represses HO-1 expression, leading to iron accumulation, mitochondrial oxidative stress, and ferroptosis in tumor-infiltrating CD8⁺ T cells. We further identify lactate as a microenvironmental trigger of STING-TOX-HO-1-mediated CD8+ T-cell ferroptosis. In mouse tumor models, engineered STING/TOX-deficient CD8⁺ T cells synergize with immune checkpoint blockade, chemotherapy, or STING agonist to enhance tumor control. These findings reveal a central pathway governing CD8⁺ T-cell ferroptosis in tumors and suggest therapeutic strategies to overcome immunotherapy resistance.

DOI: https://doi.org/10.1038/s41467-026-69350-y
Cancer Treat Res Commun. 2026 Jan 30. pii: S2468-2942(26)00031-6. [Epub ahead of print]47 101120

Securinine bolsters anti-tumor immunity by promoting CD8⁺ T cell activation.

Liangchen Gui, Wenting Song, Haowei Luo, Shuang Zhou, Ye Zhou, Liyuan Zhang, Yunhui Li, Qinlan Wang, Jin Hou.

  Securinine (SEC) is a natural alkaloid isolated from Flueggea suffruticosa, which can suppress tumor growth of some types. T cells play a critical role in anti-tumor function. However, whether SEC mediates T cell-mediated anti-tumor effects remains unknown. Here, we found that SEC treatment suppressed tumor growth and improved survival in tumor-bearing mice in vivo. SEC promotes the percentage of IFN-γ+CD8+ T cell and TNF-α+CD8+ T cell in tumor microenvironments. SEC promoted T cell-mediated cytotoxicity in B16F10-OVA and OT-I co-culture systems. The anti-tumor function of SEC was abrogated after depleting CD8+ T cells in tumor-bearing mice. Mechanistically, SEC promoted T cell receptor (TCR) activation, increased IL-2 and IFN-γ production, and enhanced mitochondrial metabolism in CD8+ T cells. Additionally, SEC combination with anti-PD-1 suppressed tumor growth and improved survival in tumor-bearing mice. Thus, SEC enhances anti-tumor immunity by promoting CD8+ T cell activation, suggesting its potential role in tumor immunotherapy.

Keywords:  Anti-tumor immunity; CD8(+) T cells; PD-1; Securinine

DOI:  https://doi.org/10.1016/j.ctarc.2026.101120
Arthritis Res Ther. 2026 Feb 13.

FASN-mediated metabolic reprogramming drives CD4+ T cell hyperactivation in Sjögren's syndrome via fatty acid oxidation-dependent oxidative phosphorylation.

Lei Ye, Xijun Wang, Junhao Yin, Huan Shi, Jiayao Fu, Baoli Wang, Lingyan Zheng.

   BACKGROUND: Sjögren's syndrome (SS) is a chronic systemic autoimmune disease in which CD4+ T cells play a critical role. Recent advances in immunometabolism suggest that metabolic reprogramming contributes to autoimmune pathogenesis. This study investigates the role of fatty acid synthase (FASN) in CD4+ T cell dysfunction in SS.
METHODS: Peripheral blood CD4+ T cells were isolated from SS patients and healthy controls. FASN expression was assessed via PCR, Western blot, and immunofluorescence. Functional and metabolic assays, including flow cytometry, Seahorse analysis, transcriptomic profiling, and global metabolomics (Q300) were performed using murine and human CD4+ T cells treated with the FASN inhibitor orlistat. Rescue experiments were conducted with oleic acid (OA) and palmitoleic acid (PA). In vivo efficacy was evaluated in NOD/LtJ and experimentally-induced SS (ESS) mouse models.
RESULTS: FASN was significantly upregulated in CD4+ T cells from SS patients and activated murine T cells, correlating with disease activity markers. Orlistat-mediated FASN inhibition suppressed T cell proliferation, activation (CD25/CD69), and glycolytic metabolism, while enhancing oxidative phosphorylation (OXPHOS), leading to elevated ROS and mitochondrial dysfunction. Metabolomics identified reduced OA and PA levels upon FASN inhibition. Exogenous OA and PA partially restored metabolic balance and activation markers. In murine models, orlistat reduced salivary gland lymphocytic infiltration, pro-inflammatory cytokines (IL-17/TNF-α), and improved salivary flow.
CONCLUSION: FASN drives CD4+ T cell hyperactivation and metabolic reprogramming in SS. Its inhibition shifts cell metabolism from glycolysis to OXPHOS, reducing inflammation and ameliorating disease in preclinical models. These results identify FASN as a potential therapeutic target for SS.

Keywords:  Fatty acid synthase (FASN); Metabolic reprogramming; Oxidative phosphorylation (OXPHOS); Sjögren’s syndrome (SS); T cells

DOI:  https://doi.org/10.1186/s13075-026-03765-2
Immun Inflamm. 2025 ;1(1): 9

Leveraging T cells for cancer immunotherapy.

Adam Bates, Nicole E Fletcher, Fei Gao, Mariana Pereira Pinho, Tao Dong.

  T cells play an essential role in tumour prevention and control, however, avoidance or disruption of anti-tumour T cell responses frequently leads to tumour progression and malignant disease. Immunotherapy aims to address this breakdown in T cell-mediated anti-tumour immunity and restore T cell function to promote the elimination of cancerous cells. Although immunotherapy has led to drastic improvements in patient prognoses across a range of clinical setting, most patients still fail to exhibit a durable therapeutic response. In this review we discuss the role of T cells in controlling tumour progression, how T cell immunity is avoided or disrupted in the context of malignant disease, and the mechanisms by which soluble, cellular, or vaccine-based immunotherapies aim to restore anti-tumour T cell responses. This review does not aim to provide a comprehensive summary of approved immunotherapies, nor does it focus on the logistical challenges faced during the development or clinical application of immunotherapy. Instead, this review aims to highlight the mechanisms by which different therapeutic approaches address, or fail to address, specific aspects of the breakdown in T cell-mediated anti-tumour immunity. This review will also discuss exciting pre- and early-stage clinical developments that may improve the therapeutic efficacy and applicability of these treatments by more comprehensively addressing the challenges faced by T cells to improve patient prognoses.
Graphical Abstract:

Keywords:  Adoptive cell transfer; Cancer; Immune checkpoint blockade; Immunotherapy; T Cells; Vaccination

DOI:  https://doi.org/10.1007/s44466-025-00007-z
bioRxiv. 2026 Jan 29. pii: 2026.01.28.702390. [Epub ahead of print]

YY1-Mediated Polycomb Group Function Safeguards Hematopoietic Stem Cells from Premature Aging.

Sahitya Saka, Junki P Lee, Yinghua Wang, Peng Liu, Yunxia Liu, Courtney Hong, Ashley Kuehnl, Lixin Rui, Michael L Atchison, Xuan Pan.

Hematopoietic stem cells (HSCs) undergo functional decline with age, characterized by myeloid-biased differentiation, loss of quiescence, and altered metabolic homeostasis. The molecular mechanisms driving these changes remain incompletely understood. Yin Yang 1 (YY1) is a multifunctional transcription factor and mammalian Polycomb group (PcG) protein that recruits PcG complexes to specific genomic loci via its 26-amino acid REPO (Recruitment of Polycomb) domain. To define the role of YY1 PcG function in adult HSCs, we generated a conditional YY1 REPO domain knockout mouse model ( Yy1 -/ΔREPO ). Deletion of the REPO domain led to premature HSC aging, with expansion of immunophenotypic HSCs but loss of long-term self-renewal capacity. Yy1 -/ΔREPO HSCs exhibited myeloid-biased output, expansion of myeloid-primed multipotent progenitors, increased myeloid colony formation, and an elevated myeloid-to-lymphoid ratio in peripheral blood. These cells displayed reduced quiescence, elevated reactive oxygen species, increased mitochondrial oxidative capacity, and enhanced β-galactosidase activity-hallmarks of cellular aging. RNA-seq demonstrated dysregulation of gene networks governing HSC metabolism. Together, these findings establish YY1 PcG activity as a key epigenetic mechanism that preserves metabolic quiescence, sustains long-term self-renewal, and delays HSC aging. Our studies reveal a fundamental PcG-dependent epigenetic mechanism that dictate cell fate decisions and function decline during HSC aging.

DOI: https://doi.org/10.64898/2026.01.28.702390
bioRxiv. 2026 Feb 05. pii: 2026.02.05.704062. [Epub ahead of print]

Querying functional drivers in primary murine naïve and memory T cells using RNP-mediated CRISPR-Cas9 Gene Deletion.

Surojit Sarkar, Yevgeniy Yuzefpolskiy, Vandana Kalia.

Cytotoxic CD8 T lymphocytes (CTL) are critical for the clearance of pathogenic cells via antigen-dependent cell lysis, thus providing protection against infectious diseases and cancers. CTLs represent one of the key targets of immunotherapies and vaccine design. While microarray and single-cell RNA sequencing of effector and memory CD8 T cells have identified several promising gene targets that may modulate CD8 T cell responses, their development is slowed down by the financial and time constraints related to the generation of germline knockout mice for further validation studies. Here we present a protocol for conducting efficient deletion of genes from activated effector, as well as resting naïve and memory primary murine CD8 T cells using RNP-based Crispr/Cas9 technology. This CRISPR modification of CD8 T cells was then adapted to study the effects of gene deletion in the context of acute memory differentiation as well as chronic exhaustion of CD8 T cells. To this end, we have titrated the necessary dose of antigen-specific CD8 T cells to study their differentiation in acute and chronic infections and confirmed the model by demonstrating rapid expansion of CRISPR mediated PD-1 ablated CD8 T cells in a chronic viral infection. Finally, by combining this methodology with a murine model of subcutaneous tumor challenge, this study provides a unique screening system for genes critical for mediating clearance of malignant tumor cells by CTLs. This study expands current technical capabilities for rapid evaluation of functional role of any candidate gene in CTL responses to infections and cancer through targeted gene deletion at any stage of CD8 T cell differentiation without the need for germline gene deletion mouse models.

DOI: https://doi.org/10.64898/2026.02.05.704062
Res Sq. 2026 Feb 02. pii: rs.3.rs-8704178. [Epub ahead of print]

CAR Signaling Informs Mechanisms to Enhance Metabolism and Function in γδ T Cells.

Daniel Abate-Daga, Xiomar Bustos Perez, Leticia Tordesillas, Elena Martinez-Planes, Miguel G Fontela, Renata Marques Rossetti, Victoria Izumi, Bin Fang, John Koomen, Eric Welsh, Patrick Hwu.

γδ T cell-based immunotherapies have gained relevance as an alternative to the conventional αβ T cell products with pre-clinical data demonstrating tumor burden reduction and mitigation of tumor-induced damage. Given that most CAR constructs were optimized for αβ T cells, we hypothesized that distinct T cell types may require tailored CAR architectures to achieve optimal function. To test this hypothesis, we conducted a systematic comparative analysis between γδ and αβ T cells transduced with a second-generation PSCA-targeting CAR (PSCA-8t28z). We found that although γδ and αβ CAR-T cells exhibit comparable cytotoxicity, they differ phenotypically. Through a system level phosphoproteomic analysis, we identified 307 phospho-sites with differential abundance between γδ and αβ CAR-T cells. Pathway enrichment analysis placed glycolysis/gluconeogenesis and TCR signaling within the top significantly overrepresented signaling networks. Functional validation studies confirmed that γδ CAR-T cells show lower glycolytic and oxidative phosphorylation capacity than αβ, and weaker Activator Protein 1 (AP-1) activation. Notably, we identified Thioredoxin-Interacting Protein as a potential actionable target to enhance γδ CAR-T cell metabolism. Finally, we designed a new synthetic co-stimulatory receptor that potentiates AP-1 activation resulting in improved in-vivo persistence. These results highlight fundamental biological differences between γδ and αβ T cells and support the development of cell type-specific receptor engineering strategies to maximize γδ CAR-T cell function and therapeutic benefit.

DOI: https://doi.org/10.21203/rs.3.rs-8704178/v1
bioRxiv. 2026 Feb 01. pii: 2026.01.28.702394. [Epub ahead of print]

Engineering "physically optimized" T cells for increased sampling of complex tumor microenvironments.

Hongrong Zhang, Zhongming Chen, Guhan Qian, Christopher D Zahm, Roberto Alonso-Matilla, Salena Fischer, Ingunn M Stromnes, Beau R Webber, Kevin W Eliceiri, David J Odde, Branden S Moriarity, Paolo P Provenzano.

Pancreatic ductal adenocarcinoma (PDA) remains highly lethal, in part, because its dense fibroinflammatory stroma restricts therapy distribution, including adoptive T cell immunotherapies where direct interactions between T and carcinoma cells are essential for effective therapy. While T cell function must be maintained once effector-target engagement occurs, without inducing co-localization subsequent cytotoxic function steps cannot be undertaken. We therefore developed a strategy to "physically optimize" T cells to more effectively sample complex tumor volumes. Informed by pharmacologic perturbations and mathematical modeling we shifted T cell phenotype through expression of constitutively activated RhoA to increase cortical contractility, activation, migration, and sampling in PDA, while showing decreases in exhaustion markers. In CAR T cells this results in more efficient targeting through decreased sampling time and increased engagement with carcinoma cells, consistent with modeling predictions. This significantly increases T cell infiltration and distribution in PDA, resulting in improved tumor control in vivo, suggesting that this is an effective strategy to overcome stromal constraints, improve tumor engagement, and enhance the therapeutic performance of engineered T cell therapies in solid tumors.

DOI: https://doi.org/10.64898/2026.01.28.702394
Nat Cardiovasc Res. 2026 Feb 09.

CXCR6 signaling as a key mediator of CD8+ T cell-driven ICI myocarditis.

Elisa Martini.

DOI: https://doi.org/10.1038/s44161-026-00784-9
Nature. 2026 Feb 11.

SLAMF6 as a drug-targetable suppressor of T cell immunity against cancer.

Bin Li, Ming-Chao Zhong, Cristian Camilo Galindo, Jiayu Dou, Jin Qian, Zhenghai Tang, Dominique Davidson, André Veillette.

Inhibitory receptors like PD-1 and CTLA-4 contribute to T cell dysfunction in cancer1-3. Monoclonal antibodies (mAbs) blocking the interactions in trans of these receptors with their ligands on cancer cells or in the tumour microenvironment lead to clinical responses in some but not all types of cancer. Signalling lymphocytic activation molecule 6 (SLAMF6, also known as Ly108) is a homotypic receptor preferentially expressed on progenitor or stem-like exhausted T (Tpex) cells, but not on terminally exhausted T (Tex) cells, as demonstrated in mouse models4-9. In contrast to Tex cells, Tpex cells retain the capacity for functional restoration after immune checkpoint blockade10-12. The role of SLAMF6 in T cells remains ambiguous, as it has both activating and inhibitory effects, complicating its evaluation as a therapeutic target. Here we find that SLAMF6 was triggered in cis by homotypic interactions at the T cell surface. These interactions elicited inhibitory effects that suppressed activation of T cells and limited anti-tumour immunity, independently of SLAMF6 expression on tumour cells. mAbs against human SLAMF6 with a robust ability to disrupt the cis interactions strongly augmented T cell activation, reduced the proportions of exhausted T cells and inhibited tumour growth in vivo. Collectively, these findings show that SLAMF6 functions exclusively as a T cell inhibitory receptor, which is triggered by cis homotypic interactions. They also position SLAMF6 as a promising target for therapies aimed at enhancing anti-tumour immunity, regardless of SLAMF6 expression on tumour cells.

DOI: https://doi.org/10.1038/s41586-026-10106-5
Cancer Res. 2026 Feb 11.

SAICAR Drives T Regulatory Cell Differentiation and FOXP3 Maintenance to Promote Immunotherapy Resistance.

Mao Li, Yaqi Chen, Anyi Liu, Qi Wu, Changsheng Huang, Da Song, Fuqing Hu, Jingqin Lan, Chen Huang, Junbo Hu, Guihua Wang.

Regulatory T cells (Tregs) within the tumor microenvironment critically undermine the efficacy of PD-1 immune checkpoint blockade. Metabolic reprogramming has emerged as a critical determinant of antitumor immunity, highlighting the need to define the metabolic cues that program Treg differentiation in cancer. Here, we identified the purine biosynthesis intermediate succinylaminoimidazole carboxamide ribose-5'-phosphate (SAICAR) as a key metabolic driver of Treg induction and resistance to anti-PD-1 immunotherapy. Mechanistically, SAICAR directly bound to the serine/threonine phosphatase PPM1A, inhibiting SMAD3 dephosphorylation and thereby sustaining TGF-β-SMAD3 signaling. Persistent SMAD3 activation enhanced FOXP3 transcription and stabilized the Treg lineage. In both human tumors and mouse models, elevated intratumoral SAICAR levels were associated with increased Treg accumulation, suppression of effector T cell function, and failure of PD-1 blockade. Genetic or pharmacological reduction of SAICAR restored antitumor immunity and sensitized tumors to PD-1 therapy. Notably, low-dose 6-mercaptopurine disrupted SAICAR-driven immunosuppression and synergized with anti-PD-1 treatment without inducing systemic immune toxicity. Together, these findings establish SAICAR as an immunometabolic regulator that links purine metabolism to immune evasion and highlight a therapeutically actionable pathway to overcome metabolite-driven resistance to immune checkpoint blockade.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-4373
J Transl Med. 2026 Feb 07.

ALDH1L1 reverses CD8+ T cell exhaustion in the oral squamous cell carcinoma microenvironment by reprogramming L-glutamate metabolism.

Guanzheng Chen, Shuqi Zhao, Lin Zhu, Shifeng Wu, Jia Kang, Minghui Mao, Zhengxue Han, Yi Qu.



Keywords:  CD8+ T cell; Immunotherapy; L-glutamate; Oral squamous cell carcinoma; Oxidative phosphorylation

DOI:  https://doi.org/10.1186/s12967-026-07812-z
bioRxiv. 2026 Feb 01. pii: 2026.01.28.701378. [Epub ahead of print]

C-terminus CD28 phosphorylation (Y218) modulates IL-2 secretion and antitumor effect of CAR-T cells.

Elena Martinez-Planes, Maria Cecilia Ramello, Miguel G Fontela, Mohammad-Reza Shokri, Lancia Darville, John Koomen, Youngchul Kim, Daniel Abate-Daga.

CD28 is a co-stimulatory component of several second-generation chimeric antigen receptor (CAR)-T cells, providing signals essential for T cell proliferation, survival, and cytokine secretion. However, the specific contribution of individual CD28 intracellular motifs to CAR-T cell function remains incompletely understood. Here, we identify tyrosine 218 (Y218) in the CD28 cytoplasmic domain as a critical regulatory site, and demonstrate that its phosphorylation is essential for optimal CAR-T cell activity. Using a 218F mutant, we show that loss of Y218 phosphorylation leads to impaired IL-2 production and abrogates antitumor efficacy. Transcriptomic profiling of 218F CAR-T cells revealed increased expression of IL-17A, IL-17F, and related cytokines, suggesting a shift toward a pro-inflammatory Th17-like phenotype that may contribute to dysfunction. Mechanistically, we demonstrate that the interleukin-2-inducible T-cell kinase, ITK, mediates Y218 phosphorylation. To further understand the role of this kinase, we engineered a novel CAR incorporating an ITK-binding motif (PYRP), which enhances ITK recruitment, increases Y218 phosphorylation, and boosts IL-2 secretion, and improves anti-tumor efficacy in vivo . Our findings underscore the functional relevance of Y218 phosphorylation in modulating CAR-T cell fate and reveal a strategy to fine-tune CAR signaling through targeted kinase recruitment to enhance therapeutic efficacy.

DOI: https://doi.org/10.64898/2026.01.28.701378
Nat Rev Immunol. 2026 Feb 13.

The ageing immune system as a driver of systemic ageing.

In Hwa Jang, Laura J Niedernhofer, Paul D Robbins, Christina D Camell.

Older individuals exhibit distinct biochemical and functional changes in their immune cells that can lead to chronic inflammation, reduced immunity to pathogens and organ dysfunction. Immune cells from older individuals acquire dysfunctional immunosenescent phenotypes that are classified as inflammatory, exhausted or senescent. Key molecular mechanisms, commonly described as hallmarks of ageing, drive the development of these phenotypes through both cell-autonomous and non-autonomous mechanisms. Importantly, the ageing immune system can drive multi-organ dysfunction and systemic ageing, suggesting that improving immune function in older individuals could have significant health benefits. Here, we review the effects of ageing on various immune cell subsets in mice and humans. We describe the molecular mechanisms that drive these functional changes and their effects on both lymphoid and non-lymphoid organs. We also discuss therapeutic approaches to improve the function of the ageing immune system to increase resilience and extend healthspan.

DOI: https://doi.org/10.1038/s41577-026-01269-3
bioRxiv. 2026 Feb 02. pii: 2026.01.29.702123. [Epub ahead of print]

Interleukin-6 restricts pre-thymic T cell lineage commitment of progenitors driving loss of SIV control.

Saleem Anwar, Naseem Sadek, Christian Michel Beusch, Ahmet F Coskun, Mohamed S Abdel-Hakeem, R Paul Johnson, Frank J T Staal, Vijayakumar Velu, Mirko Paiardini, Brandon F Keele, Guido Silvestri, David Ezra Gordon, Jeffrey A Tomalka, Sheikh Abdul Rahman.

Effective T cell reconstitution in people living with HIV is central to durable immune control and cure strategies. Sustained thymic output underpins T cell recovery and requires continuous seeding by T cell-committed progenitors originating in the bone marrow (BM). Using the SIV/rhesus macaque model, we identified a thymus-seeding progenitor (TSP; CD4⁻CD8⁻CD34⁺CD38⁻CD7⁺) in BM declining rapidly following SIV infection. This loss closely associated with reduction in T cell lineage committed differentiation of BM-derived hematopoietic stem and progenitor cells (HSPCs). Importantly, both the decline in TSPs and the impairment of pre-thymic T cell potential were strongly associated with early loss of viral control, independent of peripheral T cell dynamics. Plasma interleukin-6 (IL-6) levels robustly predicted the magnitude of TSP loss and the restriction of T cell-biased HSPC differentiation. Integrated transcriptomic and proteomic analyses revealed inflammatory imprinting of HSPCs characterized by activation of the IL-6-JAK-STAT axis, inflammasome engagement, and coordinated suppression of key T cell specification factors, including RUNX1, FYN, and ZAP70. In a nonanimal model of thymopoiesis, IL-6 exposure of rhesus macaque and human HSPCs inhibited their transition from DN1 (CD38⁻) to DN2 (CD38⁺) TSP states, indicating an early block in T cell lineage commitment. Conversely, ex vivo IL-6 receptor blockade restored thymocyte differentiation to levels comparable to untreated controls. Collectively, these findings demonstrate that pathogenic inflammation restricts pre-thymic T cell development early after infection, directly contributing to loss of viral control. These findings have important implications for understanding the mediators of anti-viral T cell immunity and HIV cure.

DOI: https://doi.org/10.64898/2026.01.29.702123
Nat Immunol. 2026 Feb 10.

Flt3L-mediated tumor cDC1 expansion enhances immunotherapy by priming stem-like CD8+ T cells in lymph nodes.

Junyun Lai, Cheok Weng Chan, Jesse D Armitage, Katherine M Audsley, Yu-Kuan Huang, Emily B Derrick, Laura S Carstensen, Christina M Scheffler, Matt E Jones, Kevin Sek, Nicola Principe, Joelle S Kim, Imran G House, Amanda X Y Chen, Kah Min Yap, Jim Middelburg, Isabelle Munoz, Dat Nguyen, Junming Tong, Thang X Hoang, Kirsten L Todd, Maximilien Evrard, Jonathan Chee, Laura K Mackay, Alistair R R Forrest, Ian A Parish, Anthony Bosco, Jason Waithman, Paul A Beavis, Phillip K Darcy.

Immune checkpoint blockade (ICB) evokes antitumor immunity through the reinvigoration of T cell responses. T cell differentiation status controls response, with less differentiated cells having an enhanced capacity to proliferate after ICB. Given that conventional type 1 dendritic cells (cDC1) maintain precursor exhausted T cells (TPEX), we hypothesized that expansion of cDC1s with Flt3L could enhance responses to ICB. Here we show that treatment with Fms-related tyrosine kinase 3 ligand (Flt3L) expands CD62L+SLAMF6+CD8+ T cells in the tumor through a mechanism that requires XCR1+ dendritic cells to traffic to the tumor-draining lymph node. The combination of Flt3L and anti-CTLA-4 enhanced therapeutic responses. Combination therapy is associated with the emergence of a CD8+ T cell subset characterized by the expression of Il21r and oligoclonal expansion of CD8+ T cells within tumors through a mechanism that is dependent on lymph node egress.

DOI: https://doi.org/10.1038/s41590-026-02419-4
Transl Stroke Res. 2026 Feb 12. 17(1): 25

Single-Cell Multiomics Decoding of TCIRG1-Mediated Cuproptosis Circuitry Rewiring Immune-Metabolic Landscape in Ischemic Stroke.

Jiajun Zhou, Ling Chen, Junheng Li, Lian Luo, Sen Shao.

  Ischemic stroke is one of the leading causes of disability and mortality worldwide. Its pathogenesis extends beyond focal cerebral ischemia-induced neuronal injury, encompassing profound immune dysregulation and secondary inflammatory responses. Recent studies have highlighted T cell dysfunction, particularly T cell exhaustion, as a critical driver of post-stroke immunosuppression and increased susceptibility to infection. However, the molecular mechanisms underlying this process remain unclear. This study focuses on a novel immunoregulatory axis involving cuproptosis, metabolic reprogramming, and T cell exhaustion, and systematically investigates the role of the key regulatory molecule TCIRG1 in post-ischemic immune homeostasis disruption. Through integrative analysis of human peripheral blood transcriptomic data (GSE58294) and single-cell transcriptomic datasets from mouse brain and bone marrow following middle cerebral artery occlusion (MCAO) (GSE174574 and GSE293098), we found that the cuproptosis pathway was markedly activated after ischemic stroke. Notably, TCIRG1 was highly expressed in T cells and co-upregulated with the cuproptosis regulator Fdx1 and T cell exhaustion markers. Metabolic flux analysis revealed that high TCIRG1 expression was associated with enhanced pyruvate metabolism and was accompanied by downregulation of MYC signaling and upregulation of Zfp644, suggesting a role for TCIRG1 in driving T cell exhaustion through metabolic reprogramming. Furthermore, CellChat analysis indicated that TCIRG1 altered intercellular communication between T cells and microglia, thereby reshaping the local immune communication network. Collectively, these findings suggest that TCIRG1 may promote T cell dysfunction via cuproptosis and metabolic pathways, contributing to immune microenvironmental imbalance after ischemic stroke. This study proposes a novel multi-axis regulatory model and provides a potential molecular target for post-stroke immunotherapy.

Keywords:  Cuproptosis; Immune microenvironment; Ischemic stroke; Metabolic reprogramming; TCIRG1

DOI:  https://doi.org/10.1007/s12975-025-01406-5
Exp Mol Med. 2026 Feb 13.

Metabolic crosstalk among cancer-associated fibroblasts, adipocytes and immune cells as an immunosuppressive tumor microenvironment driver.

Tae Hyun Kim, Seong Hun Lim, Hyesung Lee, Young Chan Chae, Do Sik Min.

The tumor microenvironment (TME) is a complex ecosystem composed of not only malignant cells but also diverse stromal and immune cell populations that collectively shape tumor behavior. Metabolism is a central regulator of the TME, orchestrating intercellular communication through altered nutrients and signaling pathways to influence both the metabolic plasticity of cancer cells and functional balance of immune populations, ultimately determining tumor progression and antitumor immunity. Although tumor-intrinsic metabolic programs have been extensively characterized, emerging evidence highlights stromal metabolism as the dominant force sculpting immune responses within the TME. Among the nonmalignant stromal constituents, cancer-associated fibroblasts and cancer-associated adipocytes have emerged as metabolically active hubs that release and redistribute key metabolites, such as lactate, fatty acids and amino acids, to modulate the activity of both tumor and immune cells. Here we integrate recent advances in the understanding of stromal-immune metabolic crosstalk and elucidates how diverse metabolic mechanisms, including nutrient competition, mitochondrial remodeling, redox imbalance and immunometabolic rewiring, collectively reinforce an immunosuppressive TME and drive therapeutic resistance. Our study highlights the emerging strategies for selectively reprogramming these metabolic networks as potential therapeutic avenues. Deciphering these multilayered interactions will establish a conceptual and mechanistic foundation for reprogramming TME, restoring immune competence and enhancing the efficacy of current immunotherapies through metabolism-targeted interventions.

DOI: https://doi.org/10.1038/s12276-026-01650-1
Front Immunol. 2026 ;17 1749526

Transcriptional and epigenetic control of human naïve CD8+ T cell activation.

Yaqiu Hu, Yuxia Du, Xuenuo Chen, Yongguo Li, Cheng Yang.

   Background: The differentiation of naïve CD8+ T cells into effector cells upon activation is essential for eliminating intracellular pathogens and cancerous cells, although the underlying epigenetic mechanisms remain incompletely characterized.
Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from healthy donors. naïve CD8+ T cells were purified and activated with α-CD3/CD28-conjugated microbeads for 0, 24, or 72 h in vitro. Flow cytometry was used to assess cytokine production and activation markers at each time point. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) was performed to identify differentially accessible chromatin regions (DARs). RNA sequencing (RNA-seq) was performed to measure gene expression. Data from ATAC-seq and RNA-seq were integrated to examine the relationship between chromatin accessibility and gene expression. Enriched pathways for DARs and differentially expressed genes (DEGs) were determined by KEGG pathway and gene ontology (GO) enrichment analysis, and transcription factor (TF) binding patterns around these genes were visualized by footprint analysis.
Results: Upon activation, naïve CD8+ T cells showed increased production of IFN-γ, TNF, and IL-2, and elevated expression of CD69 and CD95. Integrated ATAC-seq and RNA-seq analysis identified 568 and 541 dual-upregulated genes (showing both increased chromatin accessibility and expression) at 24 and 72 h post-activation, respectively. These early-response genes were enriched in pathways including pyruvate metabolism and the DNA damage response. Footprint analysis predicted the ETS and bZIP TF families as key regulators driving this coordinated chromatin and transcriptional reprogramming. Furthermore, distinct chromatin remodeling patterns were observed in gene sets associated with memory, effector function, exhaustion, and metabolism, revealing that accessibility changes did not always directly correlate with transcriptional outcomes.
Conclusion: This study defines a core set of genes and TFs that critically regulate the initial activation of human naïve CD8+ T cells. These results provide a molecular roadmap for future efforts to engineer more potent and durable CD8+ T cell responses for adoptive cell therapy.

Keywords:  epigenetic dynamics; functional differentiation; metabolic reprogramming; naïve CD8+ T cell activation; transcriptional profiles

DOI:  https://doi.org/10.3389/fimmu.2026.1749526
Immunol Lett. 2026 Feb 09. pii: S0165-2478(26)00020-9. [Epub ahead of print] 107147

Substrate availability and citrate alter TCA cycle metabolism and SLC13A3 in macrophage immune responses.

Lea Woyciechowski, Hanna F Willenbockel, Thekla Cordes.

  Cell culture media are commonly formulated to enhance cell growth and often lack the physiological nutrient composition found in human blood plasma. The impact of substrate availability on immune cell metabolism and function remains incompletely understood. Here, we demonstrate that changes in culture medium composition affect mitochondrial metabolic pathways, immune responses, and transport in macrophages. Using mass spectrometry and stable isotope tracing, we identify citrate as a mediator linking extracellular substrate availability to intracellular metabolism. We also observe increased IL-6 secretion and elevated expression of plasma membrane transporter NaDC3 (SLC13A3) under physiological carbon source conditions that are reversed when citrate is excluded from the medium. Our findings demonstrate that extracellular substrate composition influences macrophage immunometabolism and identify citrate as an extracellular signal that modulates immune responses. This work highlights the importance of physiologically relevant nutrient availability in studying and targeting immunometabolic pathways.

Keywords:  SLC13A3; citrate; immunometabolism; itaconate; mass spectrometry; mitochondrial metabolism; substrate availability; tracing

DOI:  https://doi.org/10.1016/j.imlet.2026.107147