bims-spamet 2026-09-13 papers

bims-spamet

Biomed News

on Spatial metabolomics of T cells

Issue of 2026–09–13
thirteen papers selected by
Peio Azcoaga, Katholieke Universiteit te Leuven

CD8+ T cells kill tumors by proxy.
Multicellular immunosuppressive networks in microsatellite-stable colorectal cancer: CD8+ T cell exclusion, dysfunction, exhaustion, and therapeutic implications.
Interferon regulatory factors orchestrate CD8+ T cell function (Review).
Targeting LOXL4-driven matrix stiffening with acetyldigoxin restores CD8+ T cell function in lung cancer.
Tumor-associated neutrophils and macrophages differentially affect T cell biology in the head and neck cancer tumor microenvironment.
CAFs-mediated histone lactylation reprograms cholesterol metabolism in colorectal cancer to drive CD8+ T cell immunosuppression.
Disulfidptosis as an immunometabolic rheostat in gastrointestinal cancers: tuning the balance between T Cell exhaustion and immunogenic cell death.
NAD+ Metabolic Reprogramming Drives CD8+ T Cells Senescence and Exacerbates Ulcerative Colitis.
In vivo genome-wide CRISPR screens identify FOXR1 as a suppressor of CD8+ T cell antitumor immunity.
Selenium serves as an immunomodulator adjunct to enhance the efficacy of anti-PD-1 therapy in non-small cell lung cancer.
Mitochondrial ATP promotes T cell differentiation through chromatin accessibility.
From spatial maps to treatment decisions: a roadmap for integrating explainable AI with multi-omics to guide precision immunotherapy.
Profiling tumor immune microenvironment of epithelial ovarian carcinoma.

Nat Immunol. 2026 Sep 09.

CD8+ T cells kill tumors by proxy.

DOI: https://doi.org/10.1038/s41590-026-02664-7
Front Immunol. 2026 ;17 1945393

Multicellular immunosuppressive networks in microsatellite-stable colorectal cancer: CD8+ T cell exclusion, dysfunction, exhaustion, and therapeutic implications.

Zhiyuan Xia, Haining Chen, Yefu Shen, Minghui Lin, Xihua Xie, Hao Shu, Shen Pang, Dongchao Liu, Yunfei Cao, Sen Zhang.

  Microsatellite-stable (MSS) colorectal cancer (CRC), comprising ~85-90% of cases, remains almost universally refractory to PD-1/PD-L1 monotherapy (objective response rate 5-10%), in stark contrast to the marked efficacy of immune checkpoint inhibitors (ICIs) in microsatellite-instability-high (MSI-H) disease. Here we synthesize evidence that CD8+ T cell exclusion, dysfunction, and exhaustion in MSS CRC are orchestrated not by cell-autonomous failures but by a multicellular immunosuppressive network in which tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs) cooperate through mechanistically distinct yet spatially integrated axes. We propose a four-layer hierarchical model (physical exclusion, effector dysfunction, metabolic deprivation, and active suppression) that culminates in a stereotyped three-layer spatial niche best documented in CRC liver metastases (outer mCAF belt, Tex/TSTR band, inner SPP1+ TAM aggregates). MSS-associated mechanisms include the TAM-derived COX2/PGE2/TIGIT axis driving terminal exhaustion, a functional IL-10-/IL-10+ Treg dichotomy, and CAF-mediated suppression of dendritic-cell CXCL9/10 production that blocks CXCR3+ CD8 recruitment. Effective therapeutic strategies must therefore target multiple layers simultaneously, including TAM reprogramming, stromal remodeling, precision Treg depletion, and MDSC differentiation, rather than relying on additional checkpoint inhibitors, which have proven insufficient as monotherapy or in dual combinations.

Keywords:  CD8+ T cell exhaustion; combination immunotherapy; microsatellite-stable colorectal cancer; multicellular immunosuppressive network; tumor microenvironment spatial architecture

DOI:  https://doi.org/10.3389/fimmu.2026.1945393
Int J Mol Med. 2026 Nov;pii: 311. [Epub ahead of print]58(5):

Interferon regulatory factors orchestrate CD8+ T cell function (Review).

Fa-Xi Wang, Chun-Liang Yang, Shan-Jie Rong, Qi-Jie Chen, Xiong-Tao Yue, Fei Sun.

  The fate of CD8+ T cells is dictated by epigenetic remodeling, metabolic rewiring and most critically, the transcriptional reprogramming that integrates diverse extracellular signaling pathways. Transcription factors (TFs) predetermine cell differentiation state and lineage‑specifying hub TFs are decisive for CD8+ T cell functional maturation. The present study aimed to summarize the indispensable roles of interferon regulatory factors (IRFs) in CD8+ T cell biology from early thymic development to the acquisition of distinct functional states. Alone or together with other TFs, IRFs are involved in the regulation of CD8+ T cell commitment, effector differentiation, memory maintenance and terminal exhaustion. In clinical practice, IRF family members hold potential as prognostic biomarkers and valuable therapeutic targets in CD8+ T cell‑associated immune disorders, such as tumors, transplant rejection, infection and autoinflammatory diseases.

Keywords:  CD8+ T cell; cooperative binding; interferon regulatory factor; transcriptional regulation

DOI:  https://doi.org/10.3892/ijmm.2026.5982
Sci Adv. 2026 Sep 11. 12(37): eaef1694

Targeting LOXL4-driven matrix stiffening with acetyldigoxin restores CD8+ T cell function in lung cancer.

Xuyu Gu, Yifei Zhu, Li Xu, Xinnan Xu, Kaiqi Jin, William C Cho, Qiyu Fang.

Extracellular matrix (ECM) stiffness is known to impair T cell function, yet the underpinning molecular cascade remains undefined. This paper investigates the role of lysyl oxidase-like 4 (LOXL4) in ECM stiffening and CD8+ T cell function in lung cancer. Loxl4 knockout and mouse recombinant LOXL4 protein systems, along with Piezo1, Ybx1, Acly, and Kat2a conditional knockout mouse models were established. ECM stiffness was measured by atomic force microscopy, and T cell exhaustion markers were analyzed using flow cytometry. RNA sequencing, ATAC-seq, CUT&Tag, chromatin immunoprecipitation-quantitative polymerase chain reaction, and luciferase assays were used to explore the underlying molecular mechanisms. Molecular docking was performed to explore Food and Drug Administration-approved agents targeting LOXL4. The results demonstrated that tumor-derived LOXL4 stiffened the ECM, which activates the mechanosensor Piezo1 in CD8+ T cells, triggering Ca2+ influx and downstream FAK1-YAP1 signaling. Nuclear YAP1 transactivated YBX1, which recruited the metabolic enzyme ACLY and the histone acetyltransferase KAT2A to exhaustion gene loci, epigenetically reinforcing terminal exhaustion. Conditional knockout of Piezo1, Ybx1, Acly, and Kat2a in murine CD8+ T cells abolished stiffness-induced exhaustion and suppressed tumor growth. Acetyldigoxin was identified as a high-affinity LOXL4 inhibitor. It softened the ECM, disrupted the mechanosignaling-epigenetic axis, reversed CD8+ T cell exhaustion, and synergized with anti-PD-1 blockade to achieve durable tumor regression. In conclusion, this study uncovers a mechanotransduction-to-epigenetic pathway where LOXL4-driven matrix stiffening induces CD8+ T cell exhaustion. Repurposing acetyldigoxin as a LOXL4-targeted therapy offers a promising clinical strategy to overcome ECM-mediated immunotherapy resistance in lung cancer.

DOI: https://doi.org/10.1126/sciadv.aef1694
J Leukoc Biol. 2026 Sep 08. pii: qiag122. [Epub ahead of print]

Tumor-associated neutrophils and macrophages differentially affect T cell biology in the head and neck cancer tumor microenvironment.

Xi Wang, Stefan Kasper, Hendrik Winkel, Kirsten Bruderek, Michael Pogorzelski, Eric Deuss, Sarah Theurer, Stephan Lang, Cornelius H Kürten, Sven Brandau.

  Intra-tumoral T cell activity is required for effective anti-tumor immune responses and is partly regulated by tumor-associated neutrophils and macrophages. Here, we investigated the spatial context of neutrophil/macrophage interactions with CD8+ T cells in head and neck squamous cell carcinoma. Using multiplex immunofluorescence staining of biopsies from 14 patients, we analyzed neutrophils, macrophages, and CD8+ T cells within tumor nests and stromal compartments. All three cell types were enriched in the stroma. To characterize spatial immune niches, we defined regions enriched for each cell type and analyzed their overlap. CD8+ T cells showed spatial exclusion from neutrophils, whereas macrophages co-localized with CD8+ T cells. In regions enriched for both neutrophils and CD8+ T cells, neutrophils were associated with reduced CD8+ T cell proliferation, potentially caused by contact-dependent suppression. These findings demonstrate that neutrophils and macrophages differentially shape CD8+ T cell distribution and activity within the head and neck cancer microenvironment.

Keywords:  immune niche; myeloid-derived suppressor cells; spatial analysis; stroma; tumor core

DOI:  https://doi.org/10.1093/jleuko/qiag122
J Pathol. 2026 Sep 08.

CAFs-mediated histone lactylation reprograms cholesterol metabolism in colorectal cancer to drive CD8+ T cell immunosuppression.

Huachi Li, Jun Hu, Lei Huang, Zihao Wang, Haoran Tao, Feng Cao, Min Xie.

  The progression of colorectal cancer (CRC) is critically regulated by cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME), yet the specific molecular mechanisms by which CAFs influence CRC remain unclear. This study reveals the mechanism by which CAFs promote CRC malignant progression and immune suppression through metabolic reprogramming. Findings indicate that lactate secreted by CAFs induces lactylation modifications of histone H3K9La and H3K18La, thereby upregulating the expression of key cholesterol synthesis enzymes DHCR7 and CYP51A1, which in turn enhances the malignant properties of CRC cells. In vivo and in vitro experiments confirm that inhibiting DHCR7 significantly reverses CAF-mediated tumor promotion. More importantly, this study revealed that CAF-induced CRC cells with elevated cholesterol metabolism deliver DHCR7 to CD8+ T cells via exosomes, thereby triggering mitochondrial dysfunction and driving the cellular senescence process. This senescence manifests as reduced IFN-γ secretion capacity and enhanced senescence-associated secretory phenotype (SASP). In summary, this study systematically elucidates the central role of the CAF-CRC cell-CD8+ T cell regulatory axis: CAF-derived lactate modulates cholesterol metabolism in CRC cells via histone lactylation. Subsequently, CRC cells with enhanced cholesterol metabolism deliver DHCR7 to CD8+ T cells via exosomes, inducing mitochondrial dysfunction, which in turn leads to CD8+ T-cell senescence and immunosuppression. This provides a new theoretical foundation and therapeutic rationale for metabolic-immune combination strategies in CRC. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords:  CAFs; CD8+ T cells; CRC; DHCR7; cholesterol metabolism; histone lactylation; immunosuppression

DOI:  https://doi.org/10.1002/path.70119
Front Cell Dev Biol. 2026 ;14 1932382

Disulfidptosis as an immunometabolic rheostat in gastrointestinal cancers: tuning the balance between T Cell exhaustion and immunogenic cell death.

Yachao Li, Huaijue Qiu, Zexing Li, Xiang Gao.

  Disulfidptosis is a recently characterized regulated cell death pathway driven by disulfide stress. However, its immunological consequences in the tumor microenvironment remain poorly defined. In this review, we propose a conceptual framework in which disulfidptosis functions as an immunometabolic rheostat, wherein the net outcome-T cell exhaustion versus immunogenic cell death-is critically dependent on stress intensity, kinetics, and cellular context. We hypothesize that in glucose-deprived gastrointestinal tumors, chronic sub-lethal disulfide stress may erode CD8+ T cell effector function through F-actin crosslinking at the immunological synapse, potentially involving STAT3-LDHB-G6PD-driven transcriptional reprogramming toward a TOX-associated exhaustion state. Conversely, acute synchronous tumor lysis releases damage-associated molecular patterns (DAMPs); however, productive dendritic cell (DC) cross-presentation requires that adenosine triphosphate (ATP)/adenosine conversion and high mobility group box 1 (HMGB1) redox state meet quantitative thresholds. The DPP7-GPX4 axis suppresses disulfidptosis to limit DAMP release and facilitate natural killer (NK) cell evasion, positioning it as a candidate innate immune checkpoint. We advance testable predictions for tuning this rheostat via timed nanodelivery, dietary sensitization, and DPP7/GPX4 targeting, while explicitly distinguishing correlative biomarkers from causal mechanisms. Priority experiments to validate-or falsify-the rheostat hypothesis are outlined.

Keywords:  dendritic cell cross-presentation; disulfidptosis; gastrointestinal cancers; immunometabolism; immunotherapy; innate immune checkpoint; tumor immune microenvironment; t cell exhaustion

DOI:  https://doi.org/10.3389/fcell.2026.1932382
Aging Cell. 2026 Sep;25(9): e70706

NAD+ Metabolic Reprogramming Drives CD8+ T Cells Senescence and Exacerbates Ulcerative Colitis.

Maolin Ye, Qi Zhou, Mingjia Kong, Suhan Zhao, Lingxi Lin, Lirong Chen, Jianghong Yu, Feifei Luo, Jie Liu, Jun Zhang.

  While immunosenescence is increasingly implicated in chronic inflammatory disorders, its precise pathogenic contribution to ulcerative colitis (UC) remains elusive. Here, we identify senescent CD8+ T cells as a distinct pathogenic population that exacerbates colitis, demonstrating that systemic senolytic treatment significantly attenuates disease severity. Mechanistically, nicotinamide adenine dinucleotide (NAD+) metabolic dysregulation triggers mitochondrial dysfunction and cytosolic mitochondrial DNA leakage, promoting CD8+ T cell senescence through the activation of the cGAS-STING signaling pathway. Spatial transcriptomic mapping reveals that senescent CD8+ T cells are enriched within mucosal niches experiencing NAD+ metabolic dysregulation. Crucially, this senescent-metabolic signature correlates with severe disease phenotypes and predicts non-response to biologic therapies in UC patients. Collectively, our findings uncover a critical NAD+-cGAS-STING axis driving T cell senescence, establishing the clearance of senescent immune cells as a promising therapeutic strategy for UC.

Keywords:  NAD+; immunosenescence; inflammatory bowel disease; senolytic therapy

DOI:  https://doi.org/10.1111/acel.70706
Proc Natl Acad Sci U S A. 2026 Sep 15. 123(37): e2534362123

In vivo genome-wide CRISPR screens identify FOXR1 as a suppressor of CD8+ T cell antitumor immunity.

Xue Yang, Han Ouyang, Henan Xu, Lingxiao Peng, Jianzhou Cui, Bin Zhang, Bo Huang, Chunmei Wang, Guideng Li, Xuetao Cao.

  T cell dysfunction critically limits the efficacy of T cell-based immunotherapies in solid tumors, yet the intrinsic regulators of T cell dysfunction remain incompletely understood. Through an in vivo genome-wide CRISPR screen in tumor-infiltrating CD8+ T cells, we identified Forkhead Box R1 (FOXR1) as a potent transcriptional suppressor of CD8+ T cell effector functions. Genetic ablation of FOXR1 significantly enhanced cytokine production and cytotoxic capacity in both murine and human CD8+ T cells, whereas its overexpression impaired T cell activation and effector molecule expression. Mechanistically, multiomics integration of RNA-seq, CUT&Tag-seq, and ATAC-seq revealed that FOXR1 binds directly to promoter regions of key effector genes, including IL2, GZMB, and PRF1, and represses their expression. Importantly, FOXR1 deletion in human anti-CD19 CAR T cells improved their efficacy against solid tumors, demonstrating that FOXR1 is a checkpoint of T cell effector function and targeting FOXR1 is a promising strategy to enhance CAR T cell efficacy against solid tumors.

Keywords:  CAR T cell; FOXR1; T cell dysfunction; antitumor immunity; tumor-infiltrating T cells

DOI:  https://doi.org/10.1073/pnas.2534362123
J Immunol. 2026 Aug 29. pii: vkag241. [Epub ahead of print]215(9):

Selenium serves as an immunomodulator adjunct to enhance the efficacy of anti-PD-1 therapy in non-small cell lung cancer.

Kaiyuan Guo, Hongwei Hu, Naichen Yao, Qitai Zhao, Shasha Liu, Peng Wu, Yachang Huo, Pingchuan Ma, Tianran Chen, Xinfeng Chen, Guohui Qin, Yi Zhang.

  The role of selenium in tumor progression remains controversial, and its mechanisms of action in the context of immunotherapy are poorly understood. In this study, our findings indicate that selenium supplementation did not alter immune parameters, induce organ damage under healthy conditions, or affect the growth of Lewis lung cancer cells in vitro. In tumor-bearing mice, although selenium supplementation alone significantly enhanced the infiltration of CD8+ T cells into tumors, it failed to arrest tumor growth. Further analyses revealed that selenium treatment upregulated the expression of PD-1 on CD8+ T cells and PD-L1 on tumor cells. This finding suggests that PD-1/PD-L1 engagement may impair CD8+ T cell function, thereby preventing the effective elimination of tumor cells. Consequently, selenium supplementation exhibited a strong synergistic effect when combined with anti-PD-1 therapy, yielding enhanced antitumor responses. Single-cell RNA sequencing analysis revealed that the CD8-Prf1 subpopulation expanded and displayed enhanced proliferative and cytotoxic gene signatures after treatment with a combination of selenium and anti-PD-1. Clinically, a high abundance of this subpopulation was associated with prolonged survival in patients receiving anti-PD-1 treatment. Our results indicate that selenium is a promising immunomodulator adjunct that augments CD8+ T cell function and improves the response to anti-PD-1 therapy, supporting further clinical investigation of selenium supplementation in combination with immune checkpoint inhibitors for cancer treatment.

Keywords:  combination therapy; immune checkpoint inhibitors; non-small cell lung cancer; selenium

DOI:  https://doi.org/10.1093/jimmun/vkag241
Cell. 2026 Sep 11. pii: S0092-8674(26)00996-7. [Epub ahead of print]

Mitochondrial ATP promotes T cell differentiation through chromatin accessibility.

Charles Ng, Tak Shun Fung, Dayi Li, Korbinian N Kropp, Luis F Somarribas Patterson, Alexandria Markovitz, Daniel N Weinberg, Olivia Jones, Ji-Young Kim, Guoan Zhang, Richard Koche, Mara Monetti, Huayuan Tang, Yun He, Zhengshuang Xu, Xin Cai, Ziqi Yu, Geetha Bhagavatula, Sean P Colgan, Ya-Hui Lin, Zhuoning Li, Elizabeth M Steinert, Christopher A Klebanoff, Santosha A Vardhana, Navdeep S Chandel, Lin Wu, Craig B Thompson.

  Immune elimination of chronic infection or cancer requires cytotoxic CD8+ T cells that adopt and maintain an effector phenotype. Cytotoxic T cell function is a bioenergetically demanding process. Here, we report the ability of D-α-hydroxybutyrate (DAHB) to act as a signaling molecule that increases mitochondrial ATP production and drives the conversion of proliferating T cells into cytotoxic effector cells. DAHB signaling switches ATP production from glycolysis to oxidative phosphorylation supported by fatty acid oxidation. This conversion elevates the level of a phosphagen, phosphocreatine (PCr). Both the PCr bioenergetic reserve and oxidative phosphorylation were required for T cell effector differentiation. DAHB-induced CD8 effector gene transcription was coupled to bioenergetics by BAF-complex-dependent remodeling of chromatin at effector loci. DAHB-enhanced CD8+ T cell antitumor activity both in vitro and in vivo. Together, these findings link cellular bioenergetics to the regulation of chromatin accessibility and gene expression required to support effector function.

Keywords:  BAF; CD8 T cell effector function; D-alpha-hydroxybutyrate; OXPHOS; chromatin remodeling; creatine; phosphocreatine; tumor immunology

DOI:  https://doi.org/10.1016/j.cell.2026.08.023
Biotechnol Notes. 2026 ;7 177-182

From spatial maps to treatment decisions: a roadmap for integrating explainable AI with multi-omics to guide precision immunotherapy.

Mamoudou Hamadou.

  Immunotherapy has fundamentally transformed oncology, yet durable clinical responses remain confined to a minority of patients, a therapeutic impasse that arises from the spatial complexity of the tumor microenvironment. Single-cell and spatial multi-omics now resolve this architecture at unprecedented resolution, while deep learning extracts prognostic signals from histopathology images. Yet these advances have not closed the translational gap, largely because black-box models, fragmented validation, and a lack of prospective interventional evidence prevent clinical adoption. Here, we argue that the strategic convergence of spatial multi-omics, explainable artificial intelligence (XAI), and mechanism-guided clinical trial design will provide the definitive translational bridge between tissue architecture and therapeutic decision-making. We outline a roadmap in which interpretable spatial biomarkers, derived from concept-based XAI and counterfactual reasoning, are locked as assays, prospectively validated in biomarker-stratified trials, and evaluated under real-world conditions through federated learning. We highlight the necessity of community-wide benchmarking, mandatory sharing of code and spatial data, and the deliberate reporting of negative results to discipline the field. To operationalize this integration, we introduce the Spatial Immune Engagement Index (SIEI), a distance-weighted metric that quantifies the proximity of CD8+ T cells to tumor cells using either multiplexed immunofluorescence data or concept maps derived from routine H&E imagery. This interpretable, scanner-agnostic score provides a standardized measure of immune-tumor spatial interaction that can be prospectively validated and locked as a regulated assay for clinical decision-making. This framework integrates systems biology, digital medicine, and implementation science to convert spatial tissue architecture into a routine decision-support tool, directly informing therapeutic choice, trial design, and regulatory policy.

Keywords:  Biomarker-driven clinical trials; Precision immuno-oncology; Spatial immune engagement index; Spatial multi-omics; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.biotno.2026.08.001
Oncoimmunology. 2026 Dec 31. 15(1): 2722470

Profiling tumor immune microenvironment of epithelial ovarian carcinoma.

Zeinab Dehghani-Ghobadi, Vasilis S Dionellis, Clara Traber, Jonathan S Moore, Nicolas Samartzis, Stephan Ryser, Dimitrios R Kalaitzopoulos, Nicolas Liaudet, Clothilde Ferreira, Valentine Du Bois, Paula Stancl, Rosa Karlic, Mathias Choschzick, Aurelia Noske, José L Sandoval, Eleftherios Pierre Samartzis, Intidhar Labidi-Galy.

   BACKGROUND: Epithelial ovarian carcinoma (EOC) comprises five main histological subtypes: high-grade serous (HGSOC), low-grade serous (LGSOC), clear cell (CCOC), mucinous (MOC), and endometrioid (ENOC). Each histotype harbors specific genomic alterations and clinical outcome. Few studies systematically compared the tumor immune microenvironment across the five subtypes.
METHODS: We performed 7-plex (CD45, CD8, CD68, CD163, FoxP3, CD20, and cytokeratin) sequential immunohistochemistry on a clinically annotated tissue microarray including 139 EOC representing the five subtypes and 26 borderline tumors (serous and mucinous). Digital pathology was used to quantify immune cell abundance, their spatial distribution (stroma vs tumor core), and correlation with survival.
RESULTS: Immune cells were dominated by macrophages and more abundant in the stroma than tumor core across the five subtypes, consistent with immune excluded pattern. Compared to HGSOC, CCOC displayed the highest infiltration by CD45+ leukocytes and CD68+ macrophages, particularly M2-like CD163+ cells, suggesting a macrophage-rich, immunosuppressive phenotype. LGSOC exhibited the highest infiltration by intraepithelial FoxP3+ regulatory T cells. Comparison of borderline tumors with invasive carcinoma (LGOSC and MOC) revealed that malignant progression is accompanied by loss of CD8+ T cells, enrichment in regulatory T cells and increase of CD163+/CD68+ ratio, consistent with immune evasion during tumorigenesis. There was a trend toward better survival in HGSOC highly infiltrated by lymphocytes, either intraepithelial (CD8+ and FoxP3+) or stromal (FoxP3+ and CD20+).
CONCLUSIONS: EOC is characterized by histotype-specific immune milieux defined by macrophage dominance, epithelial immune exclusion and dynamic immune remodeling during progression from borderline tumors to invasive carcinomas.

Keywords:  Ovarian cancer; borderline; immune profiling; multiplex immunohistochemistry; tumor microenvironment

DOI:  https://doi.org/10.1080/2162402X.2026.2722470