bims-spamet Biomed News
on Spatial metabolomics of T cells
Issue of 2026–05–10
seven papers selected by
Peio Azcoaga, Katholieke Universiteit te Leuven
  1. Computational identification of migrating T cells in spatial transcriptomics data.
  2. Targetable driver gene-tumor immune microenvironment axis in non-small cell lung cancer: from molecular pathological mechanisms to precision immunotherapy stratification strategies.
  3. CKS1B is a tumor-intrinsic factor driving CD8+ T cell exhaustion via maintaining persistent tumor-antigen stimulation.
  4. From immune exclusion to exhaustion: tumor microenvironment drives therapy response.
  5. CRISPR screen reveals regulators of age-associated CD8+ T cell dysfunction in cancer.
  6. NOS2 and COX2 impact the spatial landscape of CD8+ T cells in ER-breast cancer, providing novel mechanistic insight that drives tumor progression and poor survival.
  7. Artificial intelligence-powered H&E-based quantification of spatial tumor-infiltrating lymphocyte distribution identifies prognostic immune niches in colorectal cancer.
  1. JCI Insight. 2026 May 08. pii: e192718. [Epub ahead of print]11(9):
    Computational identification of migrating T cells in spatial transcriptomics data.
    Lin Zhong, Bo Li, Zhikai Chi, Siyuan Zhang, Qiwei Li, Guanghua Xiao.
      T cells are the central players in antitumor immunity, and effective tumor killing depends on their ability to infiltrate into the tumor microenvironment (TME) while maintaining normal cytotoxicity. However, late-stage tumors develop immunosuppressive mechanisms that impede T cell movement and induce exhaustion. Investigating T cell migration in human tumors in vivo could provide insights into tumor immune escape, although it remains a challenging task. In this study, we developed ReMiTT, a computational method that leverages spatial transcriptomics data to track T cell migration patterns within tumor tissue. Applying ReMiTT to multiple tumor samples, we identified potential migration trails. On these trails, chemokines that promote T cell trafficking displayed an increasing trend. Additionally, we identified key genes and pathways enriched on these migration trails, including those involved in cytoskeleton rearrangement, leukocyte chemotaxis, cell adhesion, leukocyte migration, and extracellular matrix remodeling. Furthermore, we characterized the phenotypes of T cells along these trails, showing that the migrating T cells are highly proliferative. Our findings introduce an approach for studying T cell migration and interactions within the TME, offering valuable insights into tumor-immune dynamics.
    Keywords:  Cancer; Cell migration/adhesion; Immunology; Oncology; T cells
    DOI:  https://doi.org/10.1172/jci.insight.192718
  2. Front Immunol. 2026 ;17 1801943
    Targetable driver gene-tumor immune microenvironment axis in non-small cell lung cancer: from molecular pathological mechanisms to precision immunotherapy stratification strategies.
    Wenqing Chen, Fengyan Zhang, Xin Zheng.
      Non-small cell lung cancer (NSCLC) is characterized by substantial molecular heterogeneity that critically influences the efficacy of immunotherapy. Although immune checkpoint inhibitors (ICIs) have improved outcomes in selected patients, responses vary markedly across molecular subtypes defined by targetable driver gene alterations. Increasing evidence indicates that oncogenic drivers, including EGFR, ALK, KRAS, MET, RET, and BRAF, actively shape the tumor immune microenvironment (TIME) by regulating antigen presentation, immune cell infiltration, cytokine signaling, metabolic programs, and immune checkpoint expression. These interactions generate distinct driver gene-associated immune phenotypes that underlie differential sensitivity and resistance to ICIs. Recent advances in single-cell and spatial profiling have further revealed the complexity and spatial organization of these immune landscapes. In this review, we summarize current mechanistic and clinical evidence supporting the targetable driver gene-TIME axis in NSCLC and discuss its implications for immunotherapy response, resistance, and patient stratification. This integrative framework provides a rationale for precision immunotherapy strategies and the design of biomarker-driven clinical trials.
    Keywords:  immune checkpoint inhibitors; non–small cell lung cancer; precision immunotherapy; targetable driver genes; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1801943
  3. Sci Adv. 2026 May 08. 12(19): eaec9179
    CKS1B is a tumor-intrinsic factor driving CD8+ T cell exhaustion via maintaining persistent tumor-antigen stimulation.
    Siqi Yu, Pujie Wu, Xiaoting Xie, Liang Zhu, Liping Chen, Yibo Yu, Wen Tan, Shaosen Zhang, Chen Wu, Dongxin Lin.
      T cell exhaustion is a major barrier to effective antitumor immunity, yet the tumor-intrinsic mechanisms remain poorly defined. Through single-cell and spatial proteomics analyses of esophageal squamous cell carcinoma (ESCC), we uncover two infection-like CD8+ T cell trajectories, acute-like and chronic-like responses, whose fates are dictated by the tumor cell subtypes they encounter. This concept links tumor heterogeneity to the shaping of local immune niches. Mechanistically, we identify CDC28 protein kinase regulatory subunit 1B (CKS1B) as a tumor-intrinsic inducer of chronic-like exhaustion. CKS1B forms a complex with S-phase kinase-associated protein to promote interferon regulatory factor 3 (IRF3) ubiquitination and degradation, thereby suppressing type I interferon signaling and antigen presentation. This impairs tumor cell elimination and drives progressive CD8+ T cell stimulation and exhaustion. Pharmacological blockade of the CKS1B-IRF3 interaction with 14i restores CD8+ T cell function and synergizes with immune checkpoint blockade. The tumor-intrinsic oncogenic-immune axis, which connects cancer cell signaling to immune dysfunction, is conserved across multiple malignancies, establishing a conceptual and therapeutic framework for overcoming tumor-driven T cell exhaustion.
    DOI:  https://doi.org/10.1126/sciadv.aec9179
  4. Front Immunol. 2026 ;17 1785587
    From immune exclusion to exhaustion: tumor microenvironment drives therapy response.
    Nemanja Maletin.
      The tumor microenvironment (TME) is increasingly recognized as a dynamic regulator of cancer progression and therapeutic resistance. Far from being a passive scaffold, the TME comprises diverse immune and stromal components, including cancer-associated fibroblasts, myeloid-derived suppressor cells, tumor-associated macrophages, dysfunctional vasculature, and metabolic stressors, that collectively shape tumor evolution and modulate treatment response. In this review, we explore how spatial immune exclusion, immune cell dysfunction, hypoxia, and metabolic reprogramming create barriers to effective therapy, particularly in tumors refractory to immune checkpoint inhibition. We detail the molecular and cellular mechanisms by which the TME enforces immune suppression and dampens the efficacy of chemotherapy, radiotherapy, and immunotherapy. Moreover, we highlight emerging strategies to therapeutically reprogram the TME, including anti-fibrotic therapies, vascular normalization, myeloid reprogramming, metabolic modulation, and novel platforms such as oncolytic viruses, nanoparticles, and bispecific antibodies. By dissecting both established and innovative approaches, we emphasize the importance of combinatorial and context-specific interventions aimed at increasing immune accessibility and functional competence in selected contexts, thereby improving the likelihood of therapy responsiveness. A deeper understanding of the TME's complexity offers critical opportunities to overcome resistance and improve outcomes across cancer types.
    Keywords:  cancer-associated fibroblasts; hypoxia; immune exclusion; immunotherapy; metabolic reprogramming; myeloid cells; therapy resistance; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1785587
  5. Nat Rev Immunol. 2026 May 05.
    CRISPR screen reveals regulators of age-associated CD8+ T cell dysfunction in cancer.
    Matthew Bianca, Tracy McGaha.
      
    DOI:  https://doi.org/10.1038/s41577-026-01308-z
  6. Redox Biol. 2026 Apr 27. pii: S2213-2317(26)00187-4. [Epub ahead of print]94 104189
    NOS2 and COX2 impact the spatial landscape of CD8+ T cells in ER-breast cancer, providing novel mechanistic insight that drives tumor progression and poor survival.
    Lisa A Ridnour, Robert Ys Cheng, William F Heinz, Leandro L Coutinho, Erika M Palmieri, M Cristina Rangel, Stephen K Anderson, Daniel W McVicar, Stephen M Hewitt, Stephen Tc Wong, Xiaoxian Li, Stefan Ambs, Timothy R Billiar, Sharon A Glynn, Jenny C Chang, Stephen J Lockett, David A Wink.
      Nitric oxide synthase 2 (NOS2) and cyclooxygenase 2 (COX2) tumor expression present significant obstacles for effective treatment of aggressive tumors including ER-negative breast cancer. Spatial analysis of NOS2, COX2 and CD8 expression in patient tumors has identified mechanisms of treatment inhibition that were further elucidated using the 4T1 mouse model of triple negative breast cancer and live cell culture studies. NOS2 and COX2 activate each other via a feed-forward paracrine mechanism. While NOS2 promotes cancer stemness and the formation of metastatic niches, COX2 mediates CD8+ T cell suppression. Quantitative spatial analysis has revealed NOS2/COX2 roles during the temporal progression from immune hot in low COX2 expressing tumors to three immune cold stages in the tumor microenvironment of high COX2 expressing tumors. Type 1: immune cold with stroma-restricted CD8+ T cell secretion of interferon gamma, which activates COX2 expression at the tumor margin as well as NOS2 expression at the tumor periphery. Type 2: developing immune desserts lack stroma-restricted CD8+ T cells with tumor NOS2 and COX2 restricted to the tumor periphery. Type 3: mature immune desserts exhibit abated NOS2, COX2 and CD8+ T cells, and induction of B7H4 and cancer-associated fibroblasts driven by significant tumor hypoxia and necrosis. These three types of immune desserts can coexist with each other and with immune hot regions in the same tumor. The coordinated interplay of NOS2 and COX2 indicates that targeting both these enzymes provides an effective treatment strategy that is supported by ongoing clinical trials demonstrating improved clinical outcomes in patients who have otherwise exhausted treatment options.
    Keywords:  Breast cancer; COX2; Immunosuppression; NOS2; Spatial
    DOI:  https://doi.org/10.1016/j.redox.2026.104189
  7. Cancer Immunol Immunother. 2026 May 04. pii: 163. [Epub ahead of print]75(6):
    Artificial intelligence-powered H&E-based quantification of spatial tumor-infiltrating lymphocyte distribution identifies prognostic immune niches in colorectal cancer.
    Hyun-Hee Koh, Seungeun Lee, Chiyoon Oum, Sanghoon Song, Soo Ick Cho, Sérgio Pereira, Chang Ho Ahn, Jun Yong Kim, Milim Kim, Minsun Jung.
       PURPOSE: The prognostic significance of tumor-infiltrating lymphocytes (TILs) in colorectal cancer (CRC) is well established; however, existing approaches inadequately capture their spatial distribution. We investigated the prognostic implications of TIL spatial distribution in CRC using an artificial intelligence (AI)-based method.
    METHODS: A total of 202 patients with stage II-III CRC were included. TIL densities in intratumoral (iTIL) and stromal (sTIL) regions were quantified using AI-based analysis of hematoxylin and eosin (H&E)-stained images. Based on proximity to the tumor-stromal border (TSB), TILs were subclassified into core iTIL, bounding iTIL, bounding sTIL, and outermost sTIL. Immunoscore was calculated from CD3+ and CD8+ T-cell densities in the tumor center and invasive margin.
    RESULTS: Correlations between AI-based and pathologist assessments (iTIL: r = 0.57; sTIL: r = 0.70) were comparable to inter-pathologist correlations (iTIL: r = 0.47; sTIL: r = 0.70). In univariate Cox regression analysis, bounding iTIL, bounding sTIL, and outermost sTIL were significantly associated with recurrence-free survival (RFS), whereas core iTIL was not. Composite TIL and TSB scores were developed by incorporating the prognostically significant regions. In multivariable analysis, the TIL score (p = 0.001), TSB score (p < 0.001), and Immunoscore (p < 0.001) independently predicted RFS. In microsatellite instability-high tumors, only the TSB score remained prognostically significant.
    CONCLUSION: AI-powered spatial analysis of TILs, particularly the TSB score, demonstrated prognostic performance comparable to conventional Immunoscore, thereby supporting the value of spatial immune profiling and AI-driven analysis of H&E-stained slides for improved risk stratification in CRC.
    Keywords:  Artificial intelligence; Colorectal cancer; Spatial analysis; Tumor-infiltrating lymphocyte; Tumor-stromal border
    DOI:  https://doi.org/10.1007/s00262-026-04409-9
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