bims-spamet Biomed News
on Spatial metabolomics of T cells
Issue of 2026–06–07
nine papers selected by
Peio Azcoaga, Katholieke Universiteit te Leuven
  1. T-cell exhaustion in tumor immunology: mechanisms, heterogeneity, and therapeutic strategies.
  2. T cell exhaustion landscapes and therapeutic modulation in cancer immunity.
  3. Characterization of the tumor microenvironment in locally advanced gastric cancer and identification of spatially predictive biomarkers associated with beneficial neoadjuvant immunochemotherapy.
  4. Spatial omics of immunity: Mapping cellular landscapes in tissue microenvironments.
  5. Redox-metabolic circuits as a central regulator of T cell-based immunotherapy.
  6. A spatial in situ hybridization approach to T cell clonotype analysis using T cell receptor variable gene probes.
  7. Adoptive cell therapies in solid tumors: current clinical landscape, challenges, and future directions.
  8. ALOX15-Mediated 15-HETE Uptake Drives Lung Cancer Cells Ferroptosis and Enhances CD8+ T Cell Immunity in Lung Cancer.
  9. Spatial Atlas Decodes Tumor Immune Hubs Across Cancer Types.
  1. Front Immunol. 2026 ;17 1841281
    T-cell exhaustion in tumor immunology: mechanisms, heterogeneity, and therapeutic strategies.
    Ruoxuan Wang, Yingjie Guo.
      T-cell exhaustion is a central mechanism limiting the durability of antitumor immunity and the long-term efficacy of cancer immunotherapy. Arising under persistent antigenic stimulation and sustained microenvironmental stress, exhausted CD8+ T cells undergo progressive functional impairment accompanied by stable transcriptional, epigenetic, and metabolic reprogramming. Importantly, exhaustion is now understood not as a uniform dysfunctional endpoint but as a hierarchically organized and context-dependent differentiation continuum comprising progenitor, intermediate, and terminally exhausted states with distinct degrees of plasticity and therapeutic responsiveness. This framework helps explain why immune checkpoint blockade and related therapies often produce incomplete and non-durable clinical responses, as they predominantly act on progenitor-like exhausted T cells while leaving terminally exhausted populations largely refractory to reprogramming. In this review, we integrate current knowledge of the developmental heterogeneity, molecular mechanisms, and tumor microenvironmental regulation underlying T-cell exhaustion, and examine how these features shape the efficacy of major immunotherapeutic strategies. We further suggest that future progress will depend on moving beyond attempts to globally reverse exhaustion and instead adopting state-oriented approaches that preserve progenitor-like T-cell pools, restrain terminal differentiation, and remodel the immunosuppressive tumor microenvironment.
    Keywords:  T-cell; immunology; mechanism analysis; therapeutic strategies; tumor
    DOI:  https://doi.org/10.3389/fimmu.2026.1841281
  2. Front Cell Dev Biol. 2026 ;14 1827716
    T cell exhaustion landscapes and therapeutic modulation in cancer immunity.
    Jhommara Bautista, Andrés López-Cortés.
      T cell exhaustion is a central framework for explaining why antitumor T cell responses often fail despite persistent antigen exposure and immune infiltration. Rather than a single dysfunctional endpoint, exhaustion is increasingly understood as a structured and dynamic continuum of antigen-experienced CD8+ T cell states that differ in proliferative capacity, effector potential, epigenetic constraint, metabolic fitness, and spatial distribution within tumors. This view has major therapeutic implications because clinically relevant interventions can remodel exhausted-state composition and function without fully restoring a non-exhausted identity. In this review, we examine the organization of exhausted T cell states from progenitor-like to terminal compartments and discuss how TOX-linked survival programs, epigenetic fixation, and tumor-imposed metabolic and spatial constraints stabilize exhausted fate under chronic stimulation. We highlight the role of progenitor exhausted T cells in sustaining therapeutic responsiveness, explain why reinvigoration after checkpoint blockade is often partial rather than transformative, and evaluate emerging strategies to modulate exhaustion dynamics, including combination immunotherapy and engineered control systems in CAR T cells. Together, these concepts support a shift from viewing exhaustion as a binary defect to understanding it as a constrained state system that can be measured, preserved, and selectively redirected. Defining which exhausted states remain productively controllable, and under what conditions, will be essential for developing more durable and mechanistically informed cancer immunotherapies.
    Keywords:  cancer immunotherapy; immune checkpoint blockade; progenitor exhausted T cells; tumor microenvironment; t cell exhaustion
    DOI:  https://doi.org/10.3389/fcell.2026.1827716
  3. Front Immunol. 2026 ;17 1823308
    Characterization of the tumor microenvironment in locally advanced gastric cancer and identification of spatially predictive biomarkers associated with beneficial neoadjuvant immunochemotherapy.
    Xiaohong Xu, Jun Fan, Li Peng, Zhengkai Xiang, Danju Luo, Chenggong Ma, Bo Huang, Xiu Nie, Xiaochuan Dong.
       Background: Neoadjuvant immunochemotherapy (nICT) has emerged as a promising strategy for locally advanced gastric cancer (LAGC), yet clinical responses remain heterogeneous and reliable predictive biomarkers are lacking. A comprehensive dissection of the tumor microenvironment (TME) is essential to uncover determinants of therapeutic efficacy and enable precision immunotherapy.
    Methods: We performed digital spatial profiling (DSP) using the NanoString GeoMx platform on pretreatment endoscopic biopsies from 19 LAGC patients treated with tislelizumab plus SOX chemotherapy. Multiplex fluorescence staining (PanCK, CD45, CD68) enabled compartment-specific transcriptomic analysis of tumor center regions, immune cell infiltration area, and other stromal regions. Findings were integrated with TCGA-STAD data and validated in an independent cohort (n = 20) by immunohistochemistry (IHC) for NOTUM, SERPINA3, CD8, and FOXP3.
    Results: Spatial profiling revealed distinct transcriptional programs across tumor-center regions (TC), immune cell infiltration area (MA), and other stromal regions (OTHER) compartments. High tumor-intrinsic expression of NOTUM, NKD1, and SERPINA3, together with elevated CD8+ T cell infiltration and a reduced Treg/CD3+ ratio within the TME, robustly associated with major pathological response (MPR). These spatial biomarkers were orthogonally validated by IHC in an independent cohort. In TCGA-STAD, a six-gene signature (NOTUM, APOA2, SERPINA3, NKD1, GGH, BPIFB1) correlated with prolonged survival and favorable immune infiltration, with conserved immune-modulatory patterns across multiple cancer types.
    Conclusions: This study identifies NOTUM, SERPINA3, and CD8+ T cell density as spatially resolved, clinically actionable predictors of nICT response in LAGC. Our findings underscore the power of spatial TME interrogation to uncover novel biomarkers and guide personalized immunotherapeutic strategies.
    Keywords:  biomarkers; digital spatial profiling; locally advanced gastric cancer; neoadjuvant immunochemotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1823308
  4. Curr Opin Immunol. 2026 Jun 02. pii: S0952-7915(26)00067-1. [Epub ahead of print]101 102790
    Spatial omics of immunity: Mapping cellular landscapes in tissue microenvironments.
    Ji-Eun See, Yuitian Liu, Jasmine Plummer.
      The tumor microenvironment (TME) is composed of diverse heterogeneous components and plays a crucial role in immune cell infiltration, immune evasion, and dynamic interactions between tumor cells and the immune system. A precise understanding of the TME is essential for tissue immunology research and the development of effective immunotherapies. Technologies that spatially dissect the TME and analyze it at the molecular level are increasingly important. Recently, cutting-edge, high-resolution, high-multiplex molecular profiling technologies capable of high-throughput RNA and protein profiling while incorporating spatial information have been rapidly developing. This review describes a variety of cutting-edge spatial transcriptomics and proteomics technologies, including sequencing-based spatial transcriptomics, multiplex in situ hybridization imaging-based spatial proteomics, and multiomics, which are particularly useful for tissue immunology research. Technological advances in computational tools are discussed, as well as how researchers have interpreted visualized data using our own results as examples. These technologies enable simultaneous analysis of the diverse types and functional states of immune cells in cancer tissues within the tissue architecture, providing a crucial foundation for understanding immune cell organization, function, and cell-to-cell interactions of tissue immune responses. Current spatial molecular profiling technologies still face technological limitations in resolution and analytical complexity. The lack of data standardization across diverse platforms and experimental conditions remains a significant issue, hindering the reproducibility and comparability of research results. To overcome these limitations, multiomics integrated research combining spatial transcriptomics, proteomics, and genomics data is expected to become more active in the future, which will enable a more multidimensional understanding of the TME and tissue immune environment. The introduction of artificial intelligence and machine learning technologies is expected to enable more precise interpretation of the functional status and interactions of immune cells within organizations, ultimately contributing to the development of next-generation immunotherapies.
    DOI:  https://doi.org/10.1016/j.coi.2026.102790
  5. Front Immunol. 2026 ;17 1807087
    Redox-metabolic circuits as a central regulator of T cell-based immunotherapy.
    Sarah McPhedran, Tian Zhao, Julian J Lum.
      T cell-based immunotherapies have transformed cancer treatment, yet their efficacy in solid tumors is constrained by the nutrient-poor and oxidative tumor microenvironment (TME). Accumulating evidence indicates that reactive oxygen species (ROS), methionine metabolism, and the amino acid stress sensor general control nonderepressible 2 (GCN2) are tightly interconnected regulators of T cell activation, differentiation, and effector function. In this review, we detail how these pathways form an integrated redox-metabolic circuit that dynamically tunes T cell responses to environmental stress. Physiological ROS are essential for T cell receptor signaling, glycolytic reprogramming, and cytotoxicity, whereas excessive or prolonged oxidative stress drives exhaustion and apoptosis. GCN2 links amino acid availability, particularly methionine and cysteine, to adaptive transcriptional and metabolic programs that regulate glutathione synthesis and redox homeostasis. We highlight how therapeutic manipulation of methionine availability, GCN2 signaling and ROS produces highly context-dependent outcomes across immune checkpoint blockade and adoptive cell therapy settings in solid tumors. Finally, we discuss emerging strategies to interrogate and modulate this circuit using integrated omics, CRISPR-based screening, and pharmacological approaches, emphasizing the need for context-aware and temporally controlled metabolic interventions to enhance T cell-based immunotherapies in solid tumors.
    Keywords:  GCN2; T cells; immunometabolism; immunotherapy; methionine; redox
    DOI:  https://doi.org/10.3389/fimmu.2026.1807087
  6. Cell Rep. 2026 Jun 01. pii: S2211-1247(26)00561-9. [Epub ahead of print]45(6): 117483
    A spatial in situ hybridization approach to T cell clonotype analysis using T cell receptor variable gene probes.
    Cedric Ly, Darius P Schaub, Robin Khatri, Zeba Sultana, Annika Boxnick, Zheng Song, Arthur Hube, Tobias Huber, Thorsten Wiech, Eva Tolosa, Ulf Panzer, Stefan Bonn, Christian Krebs, Immo Prinz.
      Resolving T cell clonality at single-cell spatial resolution remains a major challenge. Here, we developed an in situ hybridization panel comprising probes for immune and tissue cell types alongside comprehensive coverage of TRAV, TRBV, TRGV, and TRDV gene segments, enabling unbiased spatial mapping of T cell clones in situ. As a proof of principle, we applied this approach to human kidney biopsies from patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis and controls. Combinatorial T cell receptor variable (TRV) gene expression allowed identification of T cell clones and their spatial organization. Confined clusters of clonally related αβ T cells were found in proximity to increased numbers of antigen-presenting cells, consistent with local immune activation, while γδ T cells occupied distinct peripheral niches. Although paired αβ chain detection is currently limited, this method establishes a scalable framework for spatially resolved clonotype analysis and provides a broadly applicable tool to investigate tissue-level immune organization across diseases.
    Keywords:  CP: Immunology; autoimmune kidney disease; spatial analysis of T cell clonality; spatial transcriptomics; tissue-resident T cells
    DOI:  https://doi.org/10.1016/j.celrep.2026.117483
  7. Front Immunol. 2026 ;17 1800292
    Adoptive cell therapies in solid tumors: current clinical landscape, challenges, and future directions.
    Joe Rizkallah, Bahaa El Deen Wehbeh, Waseem Wassouf, Elio Salameh, Adnan Joumaa, Francois Jose Haddad, Lama Hamade, Nicole Charbel, Ghada M Bakri, Ali Awada, Firas Kreidieh.
      Adoptive cell therapy (ACT) has emerged as a transformative strategy in cancer immunotherapy, offering durable clinical benefit in hematologic malignancies and expanding therapeutic potential in solid tumors. However, the translation of ACT to solid malignancies remains constrained by biological, immunological, and logistical challenges. This narrative review provides an evidence based overview of the current clinical landscape of ACT in solid tumors, with a focus on chimeric antigen receptor T cell (CAR-T), tumor-infiltrating lymphocyte (TIL), and T cell receptor-engineered T cell (TCR-T) therapies. We summarize recent clinical trial outcomes, highlight tumor-specific antigen targets, and examine key determinants of therapeutic efficacy across major solid tumor types. The review discusses central obstacles limiting ACT success in solid tumors, including antigen heterogeneity, immune evasion, inadequate T cell trafficking, limited persistence, and functional exhaustion within the immunosuppressive tumor microenvironment. Mechanisms driving treatment resistance, on-target off-tumor toxicity, and immune-related adverse events such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome are critically evaluated. We further examine evolving strategies designed to overcome these barriers, including multi-antigen targeting, armored and logic-gated CAR designs, metabolic and cytokine engineering, locoregional delivery approaches, and next-generation manufacturing platforms incorporating allogeneic and gene-edited products. In parallel, the role of biomarkers, tumor microenvironment profiling, and personalized treatment selection is explored as a means to optimize patient stratification and enhance therapeutic outcomes. Advances in translational research, combination immunotherapy, and precision immuno-oncology are positioned as key drivers of the next phase of ACT development. By integrating mechanistic insights with emerging clinical evidence, this review outlines the progress, limitations, and future directions of ACT in solid tumors. It aims to provide a forward-looking framework to guide ongoing research, clinical trial design, and the rational implementation of adoptive cellular immunotherapies in solid malignancies.
    Keywords:  CAR-T cells; T cell receptor therapy; adoptive cell therapy; cancer immunotherapy; immunoregulation; solid tumors; tumor microenvironment; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.3389/fimmu.2026.1800292
  8. J Biochem Mol Toxicol. 2026 Jun;40(6): e70902
    ALOX15-Mediated 15-HETE Uptake Drives Lung Cancer Cells Ferroptosis and Enhances CD8+ T Cell Immunity in Lung Cancer.
    Jianglong Wang, Gangyi Tang, Lin Zhang.
      ALOX15 exerts tumor suppressor in numerous cancers. However, the role of ALOX15 in lung cancer is scarcely reported. This study aimed to investigate the role of ALOX15 in lung cancer. GSE225620 was used to analyzed the differentially expressed genes in lung cancer patients treated with 5-FU. Gene expression was determined using RT-qPCR, Western blot, and immunofluorescence. Ferroptosis markers were analyzed using ELISA assays. Cytokine release was determined using flow cytometry. Cellular functions were analyzed using CCK-8, transwell assay, PI staining, and flow cytometry assays. In vivo assays were conducted to further verify the role of ALOX15 and its metabolite in lung cancer. We found that ALOX15 expression was upregulated in lung cancer patients after 5-FU treatment. ALOX15 mediated the release of 15-HETE, driving lung cancer cells to ferroptosis. Moreover, ALOX15-mediated accumulation of 15-HETE stimulated anti-tumor CD8 + T cell immunity in vivo and in vitro. Mechanistically, ALOX15 upregulated TCF1, promoting the stem-like behaviors of CD8 + T cells. Moreover, upregulated TCF1 suppressed the expression of immune checkpoint genes. ALOX15 functions as an anti-tumor gene in lung cancer. TCF1-mediated 15-HETE uptake drives lung cancer cell ferroptosis and long-existing of CD8 + T cells. Therefore, ALOX15 may be a potential target for lung cancer.
    Keywords:  ALOX15; CD8 + T cell immunity; ferroptosis; lung cancer
    DOI:  https://doi.org/10.1002/jbt.70902
  9. Cancer Discov. 2026 Jun 05. OF1
    Spatial Atlas Decodes Tumor Immune Hubs Across Cancer Types.
      
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2026-058
This page is being maintained by Thomas Krichel. It was last updated on 2026‒06‒07 at 7:56.