bims-spamet Biomed News
on Spatial metabolomics of T cells
Issue of 2026–07–19
eight papers selected by
Peio Azcoaga, Katholieke Universiteit te Leuven
  1. NOSIP overexpression promotes long-term persistence of CD8+ T cells during chronic infection.
  2. Ablating Satb1 reprograms the differentiation trajectory of exhausted CD8+ T subsets to enhance antitumor immunity.
  3. The Relationship Between Neutrophil Extracellular Traps and CD8+ T Lymphocytes in Cancer: A Comprehensive Review of Current Data.
  4. Integrative machine learning reveals a TLS signature and CCL5-CCR1 axis-associated immune remodeling in breast cancer.
  5. Fibroblast-specific ablation of MHC-I antigen presentation via the IGF2 axis cripples CD8+ T cell surveillance in lung cancer.
  6. Immunological Heterogeneity in Gastric Cancer: Context-Dependent Role of CD8+ T Cells.
  7. Beyond density: mapping the functional landscapes of macrophage-T lymphocyte niches in the tumor microenvironment.
  8. MEK-dependent bioenergetic demand drives terminal CD8+ T cell exhaustion.
  1. Front Immunol. 2026 ;17 1755657
    NOSIP overexpression promotes long-term persistence of CD8+ T cells during chronic infection.
    Shihui Li, Toshikatsu Tamai, Yui Shinzawa, Sotaro Fujisawa, Yamato Tanabe, Makoto Utsunomiya, Hidetoshi Nakagawa, Junko Kurachi, Miki Koura, Eishiro Mizukoshi, Makoto Kurachi.
      Chronic antigen exposure drives CD8+ T cell exhaustion; however, strategies to maintain a long-lived, functional CD8+ T cell population under chronic stimulation remain unclear. In this study, we demonstrate that overexpression of nitric oxide synthase-interacting protein (NOSIP) enhances the persistence of antigen-specific CD8+ T cells under chronic antigen stimulation. Notably, NOSIP overexpression preserved a less differentiated CX3CR1neg subset and inhibited its progression toward an apoptosis-prone CX3CR1hi state, which was associated with reducing cell death and promoting long-term persistence. In a tumor model, NOSIP-overexpressing CD8+ T cells exhibited improved tumor control, indicating that NOSIP-mediated persistence confers superior antitumor capacity. Furthermore, NOSIP overexpression increased the responsiveness of CD8+ T cells to programmed death-ligand 1 blockade, suggesting that NOSIP may represent a promising therapeutic target.
    Keywords:  CD8+ T cells; CX3CR1 subset differentiation; NOSIP; PD-L1 blockade responsiveness; chronic antigen stimulation
    DOI:  https://doi.org/10.3389/fimmu.2026.1755657
  2. Front Immunol. 2026 ;17 1744549
    Ablating Satb1 reprograms the differentiation trajectory of exhausted CD8+ T subsets to enhance antitumor immunity.
    Linwei Wu, Haolin Jiang, Jianling Gao, Xiaolan Ji, Yu Chen, Zhenghao Ma, Xinying Li, Jin Wang, Yachen Zang, Ji Zhang, Xin Zhao, Xuefeng Wang.
       Introduction: Under chronic infections or in tumors, persistent antigen exposure drives CD8+ T cell exhaustion, a heterogeneous state encompassing a differentiation continuum from stem-like progenitor (Tpex) cells through transitory effector-like (Tex-int) cells to terminally exhausted (Tex-term) subsets. Among these T cell subsets, Tex-int cells serve as the primary population responsible for direct tumor cell killing. However, the intrinsic regulatory mechanisms that govern the Tpex-to-Tex-int transition remain incompletely defined.
    Methods: In this study, we explore the role of special AT-rich sequence-binding protein 1 (SATB1) in the differentiation of Tex-int cells from their precursors. We observed downregulation of SATB1 during Tpex-to-Tex-int differentiation in tumors. Notably, the genetic ablation of Satb1 in T cells markedly expanded the population of tumor-infiltrating CD8+ T cells (CD8+ TILs).
    Results: Ablating Satb1 not only promoted the differentiation of Tex-int cells from Tpex cells within the tumor microenvironment but also remodeled T cell differentiation in tumor-draining lymph nodes (TdLNs) by expanding the Tpex pool from tumor-specific memory CD8+ T cells (TTSM) and driving the Tpex1 to Tpex2 transition, thereby augmenting Tex-int production in tumors. Although early-stage Tex-int cells in Satb1-deficient mice displayed transient functional impairment relative to controls, this difference was no longer evident in late-stage tumors, where sustained Tex-int accumulation correlated with significantly suppressed tumor growth and prolonged survival.
    Discussion: Our results identify SATB1 as a pivotal regulator of exhausted CD8+ T cell subset differentiation and suggest its targeting as a promising strategy to expand the Tex-int population for enhanced cancer immunotherapy.
    Keywords:  Satb1; Tex-int cells; Tpex cells; effector-like Tex- int cells; stem-like Tpex cells; tumor immunity; tumor-infiltrating CD8+ T cells
    DOI:  https://doi.org/10.3389/fimmu.2026.1744549
  3. Cancers (Basel). 2026 Jun 25. pii: 2059. [Epub ahead of print]18(13):
    The Relationship Between Neutrophil Extracellular Traps and CD8+ T Lymphocytes in Cancer: A Comprehensive Review of Current Data.
    Kellyn E McKee, Hongji Zhang, Allan Tsung, Samantha M Ruff.
      Neutrophil extracellular traps (NETs) are web-like structures composed of decondensed DNA, histones, and proteins released by activated neutrophils. Originally identified as an innate defense mechanism against pathogens, NETs have since been implicated in cancer progression and immune evasion. Within the tumor microenvironment (TME), NETs suppress anti-tumor immunity through multiple mechanisms, including the physical exclusion of CD8+ cytotoxic T lymphocytes from the tumor interior and upregulation of exhaustion markers via checkpoint ligands. This review synthesizes current preclinical and clinical evidence on the interplay between NETs and CD8+ T cells across multiple malignancies, including non-small cell lung cancer, pancreatic ductal adenocarcinoma, cholangiocarcinoma, colorectal cancer, bladder cancer, hepatocellular carcinoma, skin cancer, and penile cancer. Cancer-specific mechanisms of NET-mediated immune suppression are discussed, including IL-8, IL-17, CXCL6, and TGF-β-driven NETosis pathways. Clinical data consistently demonstrate that elevated NET levels correlate with reduced CD8+ T cell infiltration, T cell dysfunction, and worse patient outcomes. Emerging therapeutic strategies targeting this axis are reviewed, including DNase I-mediated NET degradation, Peptidyl arginine deiminase 4 (PAD4) inhibition, CXCR2 blockade, and combination approaches with immune checkpoint inhibitors. These interventions have shown promise in restoring CD8+ T cell cytotoxicity and overcoming immunotherapy resistance in preclinical models. Collectively, the evidence supports the NET-CD8+ T cell axis as a promising prognostic and therapeutic target warranting further clinical investigation.
    Keywords:  CD8+ T cells; NETosis; cancer; immune evasion; immunotherapy; neutrophil extracellular traps; neutrophils
    DOI:  https://doi.org/10.3390/cancers18132059
  4. Cell Oncol (Dordr). 2026 Jul 15.
    Integrative machine learning reveals a TLS signature and CCL5-CCR1 axis-associated immune remodeling in breast cancer.
    Chuyi Wang, Pengcheng Ding, Wei Ouyang, Yunhai Ding, Meilin Lu, Tianyi Li, Yunxing Xu, Liangfeng Zheng, Kai Chen, Feiyue Ji, Min Dai, Guiyuan Gu, Xiaomin Lu.
       BACKGROUND: The transition from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) is a critical but poorly understood step in breast cancer progression. This study characterizes the dynamic remodeling of the tumor microenvironment (TME) during this transition, focusing on tertiary lymphoid structures (TLS) and chemokine signaling.
    METHODS: Using an integrated multi-omics approach-including multiplex immunofluorescence of a clinical cohort, public single-cell and spatial transcriptomics data, and a longitudinal syngeneic mouse model (EO771)-we investigated spatiotemporal TME evolution.
    RESULTS: Our findings reveal that TLS reorganization during the DCIS-to-IDC shift is closely associated with the CCL5-CCR1 axis, which is implicated in macrophage-CD8+ T cell interactions and correlates with terminal T-cell exhaustion. Longitudinal modeling confirmed CCL5 network dysregulation alongside progressive CD8+ T cell dysfunction. Through an integrative machine-learning framework, we developed a robust 21-gene TLS signature that independently predicted patient outcomes in multiple cohorts, even after adjusting for clinical confounders. Finally, molecular docking identified cucurbitacin derivatives as candidate compounds nominated by exploratory in silico analysis targeting the CCL5 network.
    CONCLUSIONS: This work highlights CCL5-CCR1 axis-related TLS dysregulation as a key spatiotemporal feature of invasion, provides a clinically applicable prognostic signature for early risk stratification, and nominates actionable targets to intercept invasive progression.
    Keywords:  Breast cancer; CCL5; Ductal carcinoma in situ; Machine learning; Tertiary lymphoid structures
    DOI:  https://doi.org/10.1007/s13402-026-01264-9
  5. Sci Adv. 2026 Jul 17. 12(29): eaee5738
    Fibroblast-specific ablation of MHC-I antigen presentation via the IGF2 axis cripples CD8+ T cell surveillance in lung cancer.
    Daqiang Song, Xiaofang Li, Qian Xiao, Hongtao Tie, Qianxue Wu, Yu Shi, Guomin Ye, Jiazheng Sun, Jiazhou Liu, Mingjing Chen, Zhu Qiu, Weiyan Peng, Long Meng, Guosheng Ren, Jing Huang, Hongzhong Li.
      How cancer-associated fibroblasts (CAFs) dictate CD8+ T cell dysfunction during lung cancer remains unclear. Through single-cell analysis of 84 human NSCLC samples, we identified insulin-like growth factor 2 (IGF2) as a key immunosuppressive factor in a specific CAF subset. IGF2+ CAF infiltration correlated with CD8+ T cell dysfunction. Fibroblast-specific IGF2 knockout enhanced antigen presentation cell-autonomously via major histocompatibility complex class I (MHC-I), boosting CD8+ T cell effector function, tumor suppression, survival, and PD-1 blockade synergy. Mechanistically, IGF2 sustained MYC signaling to up-regulate DNA methyltransferase 1 (DNMT1), which methylated the STAT1 promoter, epigenetically silencing STAT1. This impaired MHC-I presentation and CD8+ T cell activation. Clinically, high IGF2 levels associated with reduced CD8+ T cell cytotoxicity and poor outcomes. An IGF2+ fibroblast signature predicted worse response to immunotherapy in multiple cohorts. Our findings establish IGF2 as a central regulator of CAF-mediated immunosuppression and a stromal target for enhancing immunotherapy in lung cancer.
    DOI:  https://doi.org/10.1126/sciadv.aee5738
  6. Cancer Sci. 2026 Jul 12.
    Immunological Heterogeneity in Gastric Cancer: Context-Dependent Role of CD8+ T Cells.
    Xiaofei Sun, Zihao Yang, Hongtao Qu, Jinhui Wu.
      CD8+ T cell infiltration in gastric cancer shows subtype-dependent prognostic and predictive significance across TCGA molecular subtypes. Its clinical value is context-dependent and requires integrated immune profiling to guide modern chemoimmunotherapy strategies.
    DOI:  https://doi.org/10.1111/cas.70469
  7. Front Immunol. 2026 ;17 1851873
    Beyond density: mapping the functional landscapes of macrophage-T lymphocyte niches in the tumor microenvironment.
    Serena Zilio, Adrien Rouault Montecino, Malvina Seradj, Ilaria Marigo, Armelle Prévost-Blondel, Elisa Peranzoni, Nadège Bercovici.
      The spatial arrangement of tumor-associated macrophages (TAMs) and T cells within distinct microanatomical niches is emerging as a key regulator of clinical outcome in solid tumors. Here, we propose a comprehensive review that integrates spatial insights with functional studies of macrophage and T cell heterogeneity, to elucidate how the physical crosstalk and the localization of these cells in the tumor microenvironment (TME) can impact the prognosis and the response to immunotherapy and, vice versa, how diverse immunotherapies can dynamically reshape the TME immune geography. We first review the heterogeneity of macrophages and tumor-infiltrating T lymphocytes (TILs) in TME, and the different types of TAM-TIL niches recently described by multidimensional proteomics and spatial transcriptomics, addressing their impact on tumor progression and response to immunotherapy. Building on our own work, we then dissect the anti-tumoral and pro-tumoral mechanisms operating in the different types of immune hubs. Next, we examine how tumor cues and therapeutic strategies can reprogram macrophages and T cells across functional and spatial dimensions, thereby promoting TME permissive to intraepithelial T cell infiltration and clinical response. Finally, we discuss how the integration of multi-omics and artificial intelligence are transitioning immuno-oncology from a cell-centric to a niche-centric paradigm, providing a roadmap for the design of next-generation therapies that precisely reprogram cellular dialogues within the tumor microenvironment.
    Keywords:  TAM-TIL niches; cellular neighborhood; immune cell crosstalk; spatial biology; tumor microenvironment (TME); tumor-associated macrophages (TAMs); tumor-infiltrating T lymphocytes (TILs)
    DOI:  https://doi.org/10.3389/fimmu.2026.1851873
  8. Immunity. 2026 Jul 13. pii: S1074-7613(26)00263-3. [Epub ahead of print]
    MEK-dependent bioenergetic demand drives terminal CD8+ T cell exhaustion.
    Tanmana Mitra, Jahan Rahman, Madeline Hwee, Yan-Ting Chen, Ruben Jose Jesus Faustino Ramos, Hui Liu, Travis Hartman, Justin Cross, Miguel de Jesus, Morgan Huse, Valerie Longo, Pat Zanzonico, Santosha A Vardhana.
      Loss of mitochondrial function promotes CD8+ T cell dysfunction during persistent antigen encounter. Here, we examined the pathways whereby chronic antigen stimulation leads to metabolic dysfunction. Chronic T cell receptor (TCR) engagement increased ATP demand, leading to mitochondrial NADH accumulation, accumulation of reactive oxygen species, and subsequent mitochondrial dysfunction. Among TCR-dependent proximal signaling components, inhibiting the kinase MEK uniquely reduced nutrient uptake and mitochondrial NADH accumulation while restoring proliferation. Accordingly, MEK inhibition during chronic TCR stimulation reduced terminal T cell exhaustion. Mechanistically, chronic MEK activation in T cells drove ATP demand by increasing global protein synthesis rates in vitro and in vivo. MEK inhibition reversed chronic TCR stimulation-driven increases in RNA polymerase II C-terminal domain phosphorylation, reducing transcription rates at loci encoding effector- and terminal-exhaustion-associated genes while maintaining transcription of genes associated with T cell memory. Thus, MEK-dependent metabolic demand is a driver of T cell exhaustion, providing insight into how MEK inhibition enhances immunotherapy efficacy.
    Keywords:  NADH; RNA polymerase II; T cell exhaustion; bioenergetics; metabolism; mitochondria; nascent transcription; redox balance; terminal exhaustion; translation
    DOI:  https://doi.org/10.1016/j.immuni.2026.06.012
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