bims-spamet 2026-10-18 papers

bims-spamet

Biomed News

on Spatial metabolomics of T cells

Issue of 2026–10–18
eleven papers selected by
Peio Azcoaga, Katholieke Universiteit te Leuven

GPR82-mediated activation of TGF-β/SMAD signaling contributes to CD8+ T cell dysfunction in HBV-ACLF.
CRISPR-Cas9 screen identifies eIF4G2 as a regulator of CD8+ T cell dysfunction.
RNA-Binding Proteins Regulate CD8+ T Cell Biology: Mechanisms and Therapeutic Opportunities.
The narrow path to CD8+ T cell recognition of mutant p53.
CD8⁺ T Cell infiltration and spatial organization in cancer: mechanisms, barriers, and therapeutic strategies.
Platelets as non-canonical immune regulatory nodes: orchestrating T cell dysfunction and immunotherapy resistance in cancer.
Platelet-derived microparticles induce CD8+ T cell senescence in chronic kidney disease via the transfer of microRNA-550a-5p.
Loss of CLIC3 in CD8+ cytotoxic T lymphocytes is associated with immune dysfunction and poor prognosis in lung adenocarcinoma.
Innate immunity-stroma crosstalk in pancreatic cancer: overcoming spatial and metabolic barriers to immunotherapy.
Cancer-cell-derived fumarate suppresses the anti-tumor capacity of CD8+ T cells in the tumor microenvironment.
Targeting myeloid cell plasticity and metabolic reprogramming to alleviate T cell dysfunction and exhaustion-associated states and enhance immune checkpoint blockade therapy.

iScience. 2026 Oct 16. 29(10): 117599

GPR82-mediated activation of TGF-β/SMAD signaling contributes to CD8+ T cell dysfunction in HBV-ACLF.

Dongshan Yu, Zhiguo Wu, Lesheng Lin, Bo Zou, Lei Luo, Guojian Zhu, Xuebing Yao.

  Patients with acute-on-chronic liver failure (ACLF) have severe CD8+ T cell dysfunction. This study examined G protein-coupled receptor 82 (GPR82) in CD8+ T cell exhaustion in hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). Using GEO analysis, clinical samples, GPR82 manipulation, transforming growth factor beta (TGF-β)/SMAD intervention, dual-luciferase assays, and a mouse hepatitis virus strain 3 (MHV-3) mouse model, we found GPR82 overexpression in ACLF liver and HBV-ACLF CD8+ T cells, correlating with T cell exhaustion. GPR82 knockdown enhanced CD8+ T cell function, while overexpression had opposite effects. Mechanistically, lysophosphatidylcholine (LysoPC) upregulated GPR82 transcription via TGF-β/SMAD1, and elevated GPR82 further activated TGF-β/SMAD, forming a positive feedback loop. In vivo, GPR82 knockdown partially restored CD8+ T cell function and alleviated liver injury in the MHV-3 mouse model. These findings indicate GPR82 promotes CD8+ T cell exhaustion via TGF-β/SMAD, and the LysoPC-GPR82 loop offers insight into ACLF immune dysfunction, suggesting GPR82 as a potential biomarker and therapeutic target.

Keywords:  CD8⁺ T cells; GPR82; HBV-ACLF; LysoPC; TGF-β/SMAD signaling; cytokines

DOI:  https://doi.org/10.1016/j.isci.2026.117599
J Immunol. 2026 Oct 01. pii: vkag187. [Epub ahead of print]215(10):

CRISPR-Cas9 screen identifies eIF4G2 as a regulator of CD8+ T cell dysfunction.

Erin A Holcomb, Long Jiang, Ashley N Pearson, Jadyn James, Akshay Tate, Zhuwen Wang, Anwesha Dasgupta, Jim Clauwaert, Nicholas D Armas, Ameer L Elaimy, Dilrukshika S W Palagama, Samantha K Goodwin, Matthew J Kwiatkowski, Miguel Gijón, Meredith A Morgan, Adam H Courtney, Shannon A Carty, Amanda K Huber, Weiping Zou, John R Prensner, Michael D Green.

  CD8+ T cells directly target and kill cancer cells and are required for effective antitumor immunity. However, CD8+ T cells may become dysfunctional when exposed to chronic antigen stimulation during cancer. Dysfunction is characterized by reduced proliferation, increased expression of inhibitory receptors, and impaired effector function, yet the genetic mechanisms controlling dysfunction remain poorly understood. Therefore, we developed a murine ex vivo chronic stimulation model that recapitulates features of CD8+ T cell dysfunction observed within the tumor microenvironment. By coupling this system with genome-wide CRISPR-Cas9 loss-of-function screening, we discovered that the progression of murine CD8+ T cells to a dysfunctional state required eIF4G2, a noncanonical mRNA translation factor. Deletion of eIF4G2 restored CD8+ T cell survival and proliferation during chronic stimulation conditions in vitro. Transcriptomic, proteomic, and flow cytometric analyses revealed that eIF4G2 deletion shifts CD8+ T cell phenotype from a dysfunctional state to a proliferative state. eIF4G2 depletion reduced oxidative stress, lipid peroxidation, and accumulation of misfolded protein aggresomes during chronic in vitro stimulation. Finally, eIF4G2-depleted cells mediated enhanced tumor control in a murine model of melanoma. These data suggest that targeting eIF4G2 may promote CD8+ T cell resilience and improve therapeutic antitumor immunity.

Keywords:  T cell; adoptive cell therapy; immunotherapy; tumor microenvironment; tumor-infiltrating lymphocyte

DOI:  https://doi.org/10.1093/jimmun/vkag187
Expert Rev Mol Med. 2026 Oct 15. 28 e45

RNA-Binding Proteins Regulate CD8+ T Cell Biology: Mechanisms and Therapeutic Opportunities.

Ashwin B R Kumar.

   BACKGROUND: Immune-related diseases contribute substantially to global morbidity and mortality. CD8+ T cells play a critical role in adaptive immunity by eliminating virus-infected and malignant cells. The biology of CD8+ T cells is governed by tightly regulated gene expression programs, and disruption of these programs can lead to diverse immunopathologies and malignancies. This article evaluates our current understanding of post-transcriptional and translational regulation of gene expression in CD8+ T cells by RNA-binding proteins.
METHODS: Relevant and up-to-date literature was critically analysed to gain mechanistic insights into the roles of RNA-binding proteins in CD8+ T cell biology and to identify key knowledge gaps and future directions, with particular emphasis on therapeutic implications.
RESULTS: RNA-binding proteins regulate diverse aspects of CD8+ T cell biology, including differentiation, cytokine production, stress adaptation and proliferation. Recent studies further reveal how dysregulated expression and function of RNA-binding proteins contribute to hyperinflammation and haematological malignancies.
CONCLUSIONS: RNA-binding proteins are emerging as key post-transcriptional and translational checkpoint regulators of CD8+ T cell biology and represent promising therapeutic targets for immune-related diseases; however, substantial mechanistic and disease-specific studies, as well as rigorous translational validation, are required before RNA-binding protein-targeted therapeutic strategies can be safely and effectively advanced into clinical practice.

Keywords:  CAR-T cell immunotherapy; CD8+ T cells; RNA-binding proteins; immunological memory; post-transcriptional regulation of gene expression; tumour-infiltrating lymphocytes

DOI:  https://doi.org/10.1017/erm.2026.10075
Immunity. 2026 Oct 13. pii: S1074-7613(26)00395-X. [Epub ahead of print]59(10): 2617-2619

The narrow path to CD8+ T cell recognition of mutant p53.

Evan W Newell.

Shared cancer driver mutations offer attractive targets for cancer immunotherapy, but their expression does not necessarily put them within the reach of a T cell response. In this issue of Immunity, Haratani et al. identify distinct barriers to the processing, presentation, and recognition of neoantigens generated from mutant p53 that help explain this gap.

DOI: https://doi.org/10.1016/j.immuni.2026.09.020
Mol Biomed. 2026 Oct 10. pii: 201. [Epub ahead of print]7(1):

CD8⁺ T Cell infiltration and spatial organization in cancer: mechanisms, barriers, and therapeutic strategies.

Lylou Milian, Mannon Geindreau, Cassandre Pignol, Frédérique Vegran.

  The infiltration of tumors by CD8⁺ T lymphocytes is a critical determinant of antitumor immunity and response to immunotherapy. However, the presence of tumor-specific CD8⁺ T cells does not necessarily translate into effective tumor control, as multiple biological barriers can prevent their recruitment, spatial distribution, persistence, and functional activity. This review provides a comprehensive overview of the multistep mechanisms regulating CD8⁺ T-cell infiltration, from immune priming and systemic trafficking to vascular entry, intratumoral migration, and tissue residency. We discuss how alterations in chemokine networks, dysfunctional tumor vasculature, extracellular matrix remodeling, stromal barriers, and immunosuppressive signals collectively drive immune exclusion and resistance to therapy. Unlike previous reviews that have focused on individual aspects of T-cell trafficking, tumor immune contexture, or immune exclusion, we integrate these interconnected mechanisms as successive biological checkpoints and link them to therapeutic strategies aimed at overcoming specific barriers. These include restoration of antigen presentation and dendritic cell function, reprogramming of chemokine pathways, vascular normalization, stromal remodeling, innate immune activation, and induction of tertiary lymphoid structures. This integrated framework highlights why increasing CD8⁺ T-cell infiltration alone may be insufficient and supports the development of rational, sequential, and spatially guided combination strategies. Advances in spatial transcriptomics, single-cell technologies, and multiplex imaging are expected to enable personalized identification of dominant immune barriers and rational design of combination therapies. Ultimately, the goal is shifting from simply activating T cells toward engineering tumor ecosystems that support sustained CD8⁺ T-cell infiltration, organization, and effector function.

Keywords:  CD8+ T cells; Chemokines and chemokine receptors; T cell recruitment; Tumor Microenvironment; Tumor infiltration

DOI:  https://doi.org/10.1186/s43556-026-00612-3
Apoptosis. 2026 Oct 15. pii: 248. [Epub ahead of print]31(11):

Platelets as non-canonical immune regulatory nodes: orchestrating T cell dysfunction and immunotherapy resistance in cancer.

Qian Huang, Shuqin Zhang, Ruoshui Liu, Zhijiang Chen, Liming Deng, Jiahong Liao, Yiran Tian, Mi Zou, Jie Peng, Liang Hao.

  Immune checkpoint inhibitors (ICIs) have reshaped cancer treatment; however, durable clinical benefit remains limited by primary and acquired resistance, frequently associated with T cell dysfunction within an immunosuppressive tumor microenvironment. Beyond their classical role in hemostasis, platelets have emerged as active immune modulators capable of shaping antitumor T cell responses. Accumulating evidence indicates that platelets engage T cells through contact-dependent receptor-ligand interactions, immunomodulatory soluble factors, and the transfer of checkpoint-associated extracellular vesicles, thereby reinforcing dysfunctional T cell states and constraining responses to immune checkpoint blockade. In this review, we synthesize current mechanistic insights into platelet-T cell crosstalk, delineate its differential impact across T cell subsets, and integrate these processes into a broader framework of immune evasion and immunotherapy resistance. We further discuss emerging translational strategies aimed at modulating platelet immune functions, including antiplatelet drug repurposing, selective targeting of platelet-immune interfaces, and metabolic interventions to restore T cell fitness. Collectively, this work reframes platelets as non-canonical immune regulatory nodes and highlights platelet-T cell interactions as a therapeutically actionable layer of immune regulation with implications for improving and personalizing cancer immunotherapy.

Keywords:  Antiplatelet strategies; Immune checkpoint inhibitor resistance; Platelets; Platelet–T cell crosstalk; T cell dysfunction; Tumor microenvironment

DOI:  https://doi.org/10.1007/s10495-026-02459-z
Exp Mol Med. 2026 Oct 16.

Platelet-derived microparticles induce CD8+ T cell senescence in chronic kidney disease via the transfer of microRNA-550a-5p.

Yuewen Sun, Qigang Lan, Yaqin Wang, Minhua Xie, Xinyi Wu, Liangjing Lv, Qing Xin, Jun Chen, Xiaoyi Zhong, Mengying Yao, Shuiqin Gong, Siyan Zhou, Junping Wang, Jinghong Zhao.

Infection is a leading cause of mortality in patients with chronic kidney disease (CKD), in which T cell dysfunction is considered a typical feature. Although platelets are active participants in immune response, their role in regulating T cell function in patients with CKD remains unclear. In this study, we demonstrate that CD8+ T cell senescence may be a major contributor to the immunosuppressed state of patients with CKD, and that platelets derived from patients with CKD can induce premature CD8+ T cell senescence, potentially through mediating mitochondrial dysfunction. Further investigations reveal that platelet-derived microparticles (PMPs) from patients with CKD promote CD8+ T cell senescence via transferring miR-550a-5p, thereby decreasing PMPCB expression and inducing NDUFS8 cleavage failure. Finally, inhibition of miR-550a-5p and pretreatment with nicotinamide mononucleotide are capable of preventing platelet-induced CD8+ T cell senescence in CKD patients. Collectively, these findings suggest that the ectopic transient expression of platelet-derived miR-550a-5p in CD8+ T cells promotes cellular senescence by regulating the PMPCB-NDUFS8 axis, which can be exploited to treat CKD-associated immunosenescence.

DOI: https://doi.org/10.1038/s12276-026-01876-z
Front Oncol. 2026 ;16 1975159

Loss of CLIC3 in CD8+ cytotoxic T lymphocytes is associated with immune dysfunction and poor prognosis in lung adenocarcinoma.

Yinglong Li, Yidan Nie, Zhigang Han, Tingting Yu.

   Background: Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer, with a dismal prognosis partly attributed to immune evasion mediated by T cell dysfunction within the tumor microenvironment. However, the molecular determinants governing CD8+ cytotoxic T lymphocyte functional competence remain incompletely understood. Chloride intracellular channel 3 (CLIC3) has been implicated in cancer progression, but its role in T cell immunity within the LUAD TME is unknown.
Methods: We performed single-cell RNA sequencing on tumor tissues from nine LUAD patients spanning three pathological stages (adenocarcinoma in situ [AIS], minimally invasive adenocarcinoma [MIA], and invasive adenocarcinoma [IAC]), integrated with spatial transcriptomics, TCGA-LUAD bulk RNA-seq analysis, and flow cytometric validation in an independent cohort of 32 LUAD patients. Functional module scoring and pseudotime trajectory analysis were applied to characterize CLIC3-associated CTL functional states.
Results: CLIC3 was predominantly expressed in CTLs and showed a stage-associated decline from AIS to MIA to IAC. CLIC3+ CTLs exhibited significantly higher module scores for cytotoxicity, cytoskeleton remodeling, interferon signaling, and chemotaxis compared to CLIC3- CTLs. Pseudotime trajectory analysis indicated that CLIC3+ cells were positioned at one end of the inferred transcriptional continuum, corresponding to a functionally active state, while CLIC3- cells were positioned at the other, corresponding to a dysfunctional state, accompanied by a decline in CD247, GZMB, PRF1, and TNF along the trajectory. High CLIC3 expression in TCGA-LUAD was associated with significantly longer overall survival. Flow cytometry showed a stage-associated decrease in CLIC3 expression on CD8+ T cells with increasing tumor invasiveness and poor differentiation.
Conclusions: CLIC3 serves as a novel marker of CTL functional competence in LUAD, and its stage-associated downregulation reflects T cell dysfunction during tumor progression. CLIC3 expression in CD8+ T cells may represent a predictive biomarker for immunotherapeutic response and a potential target for restoring T cell function in LUAD.

Keywords:  CLIC3; T cell exhaustion; cytotoxic T lymphocytes; lung adenocarcinoma; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2026.1975159
Front Immunol. 2026 ;17 1942345

Innate immunity-stroma crosstalk in pancreatic cancer: overcoming spatial and metabolic barriers to immunotherapy.

Yulong Hou, Zhenhua Tan.

  Pancreatic ductal adenocarcinoma (PDAC) exhibits profound resistance to current immunotherapies, a challenge largely attributed to its uniquely immunosuppressive and desmoplastic tumor microenvironment (TME). At the heart of this therapeutic recalcitrance lies the dynamic, bidirectional crosstalk between innate immune cells-particularly tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs)-and stromal components, notably cancer-associated fibroblasts (CAFs). This review comprehensively delineates how the innate immunity-stroma axis establishes formidable spatial and metabolic barriers that thwart effective antitumor immunity. Spatially, dense collagen matrices, periductal fibroblast organization, and neutrophil extracellular traps (NETs) create physical checkpoints that exclude cytotoxic CD8+ T cells and natural killer (NK) cells from tumor nests. Metabolically, elevated lactate, cholesterol dysregulation, adenosine accumulation, and altered polyamine metabolism synergistically paralyze effector lymphocytes while driving immunosuppressive myeloid polarization. We highlight the key molecular networks orchestrating this pathological crosstalk, including the NF-κB, IL-1β, JAK/STAT3, and TGF-β signaling pathways. Furthermore, we summarize emerging therapeutic strategies designed to dismantle these barriers, encompassing macrophage reprogramming, CAF modulation, and metabolic interventions. Finally, we discuss the multidimensional "3D+R" framework-integrating de-desmoplasia, de-adenosine, de-novo antigen presentation, and rational sequencing-as a conceptual roadmap for rationally designed combination therapies to overcome PDAC immunotherapy resistance.

Keywords:  cancer-associated fibroblasts (CAFs); immunotherapy resistance; innate immunity; pancreatic ductal adenocarcinoma (PDAC); tumor microenvironment (TME)

DOI:  https://doi.org/10.3389/fimmu.2026.1942345
Cell Metab. 2026 Oct 13. pii: S1550-4131(26)00443-2. [Epub ahead of print]

Cancer-cell-derived fumarate suppresses the anti-tumor capacity of CD8+ T cells in the tumor microenvironment.

Jie Cheng, Jinxin Yan, Ying Liu, Jiangzhou Shi, Haoyu Wang, Hanyang Zhou, Yinglin Zhou, Tongcun Zhang, Lina Zhao, Xianbin Meng, Haipeng Gong, Xinxiang Zhang, Haichuan Zhu, Peng Jiang.

DOI: https://doi.org/10.1016/j.cmet.2026.10.006
Biomark Res. 2026 Oct 16. pii: 142. [Epub ahead of print]14(1):

Targeting myeloid cell plasticity and metabolic reprogramming to alleviate T cell dysfunction and exhaustion-associated states and enhance immune checkpoint blockade therapy.

Mingxing Wang, Jian Chen, Zhonghua Wu, Zhiying Wang, Zhixian Zhong, Yi Zhong.

  Immune checkpoint blockade (ICB) therapy has achieved clinical progress in various malignancies, yet primary and acquired resistance limits its efficacy in solid tumors. Myeloid cells in the tumor microenvironment (TME), including tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), and myeloid-derived suppressor cells (MDSCs), undergo metabolic reprogramming under hypoxia and nutrient stress. They impair effector T cell function and may contribute to exhaustion-associated states via nutrient competition, release of toxic metabolites, and formation of physical barriers, representing a critical resistance mechanism. This review summarizes the spatiotemporal heterogeneity of myeloid cells and the metabolic networks underlying their immunosuppressive phenotypes, focusing on dysregulated lipid and cholesterol metabolism, amino acid remodeling, the glycolytic switch, and subcellular stress responses. We analyze how metabolic dysregulation causes T cell dysfunction and, in defined contexts, contributes to exhaustion-associated transcriptional programs through nutrient competition, toxic metabolite accumulation, and upregulation of inhibitory receptor ligands, and summarize intervention strategies targeting myeloid recruitment, phenotypic remodeling, metabolic reprogramming, and pathological structures combined with ICB. We discuss challenges of efficacy heterogeneity and safety in clinical translation, and highlight the prospects of multi-omics and computational biology in guiding next-generation combination immunotherapy. Understanding myeloid metabolic plasticity may provide a basis for overcoming immunotherapy resistance and establishing precise synergistic strategies.

Keywords:  Combination immunotherapy; Immune checkpoint inhibitors; Metabolic reprogramming; Myeloid cells; T cell dysfunction; T cell exhaustion; Tumor microenvironment

DOI:  https://doi.org/10.1186/s40364-026-01011-0