bims-spamet 2026-10-04 papers

bims-spamet

Biomed News

on Spatial metabolomics of T cells

Issue of 2026–10–04
eight papers selected by
Peio Azcoaga, Katholieke Universiteit te Leuven

INHBB Promotes Colorectal Cancer Progression by Inducing CD8+ T Cell Exhaustion via the ACVR2B-SMAD Signaling Axis.
Macrophage Trogocytosis of Tumor Cells Drives the Immunosuppression of Tumor Microenvironment.
Metabolic dysfunction and GZMK+ CD8+ T-cell remodeling in hepatocellular carcinoma: an evidence-stratified, hypothesis-generating review.
SPRED2 Negatively Regulates CD8+ T Cell-Mediated Antitumor Immunity in Breast Cancer.
Coupling and uncoupling cell cycle and metabolism in CD8+ T cells.
Contextual control of CD8+ T cell priming by dendritic cell subsets in tumor and inflammatory microenvironments.
Immune remodeling of tumor-draining lymph nodes: mechanistic determinants of checkpoint blockade responsiveness.
Macrophage-CD8⁺ T Cell Spatial Coupling Defines an Innate-Adaptive Injury Niche in Human Checkpoint Inhibitor Hepatotoxicity.

Cancer Sci. 2026 Sep 28.

INHBB Promotes Colorectal Cancer Progression by Inducing CD8+ T Cell Exhaustion via the ACVR2B-SMAD Signaling Axis.

Guanghui Liu, Yuanhua Liu, Hongchao Zhao, Junfeng Sun, Hongwei Yang, Qingqing Ding.

  To investigate the expression pattern, biological functions and regulatory mechanisms of inhibin beta B (INHBB) in colorectal cancer (CRC), and to clarify its role in mediating CD8+ T cell exhaustion via the INHBB-ACVR2B-SMAD signaling axis for identifying a novel therapeutic target in CRC targeted immunotherapy, we analyzed the expression profile and prognostic value of INHBB in CRC tissues using The Cancer Genome Atlas database. Stable INHBB knockdown and overexpression CRC cell lines were constructed, and the malignant phenotypes were evaluated by Transwell assays, flow cytometry and other functional experiments. The interaction between INHBB and ACVR2B was verified by co-immunoprecipitation and immunofluorescence, and the in vivo regulatory effects of this pathway were determined using mouse xenograft tumor models combined with SMAD inhibitors. INHBB was upregulated in CRC tissues and associated with poor prognosis. Functional assays demonstrated that INHBB promoted the proliferation and invasion and suppressed the apoptosis of CRC cells. Mechanistically, INHBB bound to ACVR2B on CD8+ T cells, activated SMAD signaling, and triggered CD8+ T cell exhaustion, whereas blockade of the SMAD pathway reversed INHBB-mediated immunosuppression and tumor progression. Collectively, INHBB dually regulates the malignant phenotypes of CRC cells and CD8+ T cell function through the INHBB-ACVR2B-SMAD axis, and targeting this axis may represent a promising therapeutic strategy for CRC immunotherapy.

Keywords:  CD8+ T cell exhaustion; INHBB; SMAD signaling pathway; colorectal cancer; tumor immune microenvironment

DOI:  https://doi.org/10.1111/cas.70542
Adv Sci (Weinh). 2026 Sep 30. e77518

Macrophage Trogocytosis of Tumor Cells Drives the Immunosuppression of Tumor Microenvironment.

Chao Liang, Jiaqi He, Wan-Ru Zhuang, Yao Lei, Yanru Jiang, Xianbin Ma, Pan Liu, Zhujun Jiang, Yongheng Li, Hai-Yan Xie.

  Despite considerable advances in cancer immunotherapy, the persistent immunosuppressive tumor microenvironment (TME) seriously limits its performance in solid tumors. Here, we reveal that trogocytosis-an intercellular membrane transfer process-between tumor-associated macrophages (TAMs) and cancer cells serves as a critical mechanism driving this immunosuppression. We demonstrate that trogocytosis efficiency, inversely correlated with tumor cell cortical stiffness, varies substantially across cancer types and dictates immunosuppressive intensity through upregulation of CXCL5 and Arg-1, leading to CD8+ T cell exhaustion. Importantly, this mechano-immunological axis is conserved in humans, as evidenced by study with human cell lines and a strong correlation between trogocytosis markers and T cell exhaustion in clinical patient samples. Increasing tumor cell stiffness with simvastatin effectively suppressed trogocytosis, reversed T cell dysfunction, and synergistically enhanced the efficacy of adoptive T cell therapy. These findings establish macrophage trogocytosis as a fundamental driver of immunosuppressive heterogeneity and highlight its targeting as a promising strategy to potentiate cancer immunotherapy.

Keywords:  T cell exhaustion; cortical stiffness; immunosuppressive heterogeneity; trogocytosis; tumor‐associated macrophages

DOI:  https://doi.org/10.1002/advs.77518
Front Immunol. 2026 ;17 1963310

Metabolic dysfunction and GZMK+ CD8+ T-cell remodeling in hepatocellular carcinoma: an evidence-stratified, hypothesis-generating review.

Qianqian Zhong, Wanruo Lyu, Jieying Li, Yiming Song, Yunxin Huang, Chunbin Wang, Juling Ji.

  Type 2 diabetes mellitus and metabolic dysfunction associated steatotic liver disease contribute to the growing burden of hepatocellular carcinoma, yet their effects on hepatic antitumor immunity remain incompletely defined. Recent single-cell and spatial profiling studies indicate that hepatocellular carcinoma contains diverse CD8+ T cell states, including cytotoxic, exhausted, tissue-resident, progenitor-like, and transitional phenotypes. This review synthesizes evidence linking hyperglycemia, insulin resistance, lipotoxic injury, chronic inflammation, fibrosis, altered antigen presentation, stromal remodeling, chemokine signaling, and nutrient availability to CD8+ T-cell remodeling in HCC arising in the context of metabolic dysfunction. Particular attention is given to GZMK+ CD8+ T cells, which may reflect non-terminal differentiation, inflammatory adaptation, or transitional immune states rather than conventional cytotoxic effector function. Although GZMK-high CD8+ T cell populations have been reported in hepatocellular carcinoma and therapy-associated immune contexts, direct evidence that type 2 diabetes induces these cells in the liver remains limited. This review specifically examines GZMK+ CD8+ T-cell states within the immunometabolic context of HCC, distinguishes direct hepatic and tumor evidence from extrapolated findings in metabolic liver disease and other inflammatory conditions, and proposes a testable framework for phenotypic, spatial, and functional validation. Integrated single-cell, spatial, protein level, T cell receptor clonality, functional, and clinical studies are needed to define their biological significance and translational value.

Keywords:  CD8+ T cells; GZMK; hepatocellular carcinoma; immunometabolism; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1963310
Adv Sci (Weinh). 2026 Sep 27. e77909

SPRED2 Negatively Regulates CD8+ T Cell-Mediated Antitumor Immunity in Breast Cancer.

Miao Tian, Teizo Yoshimura, Kun Zhao, Chunning Li, Tong Gao, Ziyi Wang, Masayoshi Fujisawa, Toshiaki Ohara, Akihiro Matsukawa.

  Activation of the RAS/RAF/ERK pathway is crucial for adaptive immunity. Here, we provide evidence that Sprouty-related EVH1 domain containing 2 (SPRED2), an endogenous inhibitor of this pathway, negatively regulates CD8+ T cell-mediated antitumor immunity in breast cancer. In EO771 and 4T1 mouse models, Spred2-/- mice exhibit reduced tumor growth, with lower endpoint lung metastatic burden in the 4T1 model, accompanied by increased T-cell infiltration and activation. Spred2-/- T cells show enhanced cytokine expression, proliferation, survival, in vitro cytotoxicity, and memory-like phenotypes, particularly among CD8+ T cells. Adoptive transfer of Spred2-/- CD8+ T cells into tumor-bearing wild-type hosts similarly reduces endpoint lung metastatic burden. MEK inhibition with U0126 attenuates increased interferon-gamma and granzyme B expression in Spred2-/- CD8+ T cells. Transcriptomic analyses reveal an inverse correlation between SPRED2 expression and antitumor CD8+ T cell states in both humans and mice. In tumor-infiltrating T cells from patients with breast cancer, SPRED2low T cells show enriched effector and cytotoxicity programs and are associated with "immune-hot" tumors, whereas survival associations vary with CD8+ T cell context. Collectively, these findings suggest that SPRED2 functions as a cell-intrinsic negative regulator of CD8+ T-cell activation and highlight its potential as a therapeutic target to enhance T cell-based cancer immunotherapy.

Keywords:  CD8+ T cells; MAPK/ERK; breast cancer; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.1002/advs.77909
Trends Immunol. 2026 Sep 29. pii: S1471-4906(26)00256-5. [Epub ahead of print]

Coupling and uncoupling cell cycle and metabolism in CD8+ T cells.

Floortje J van Haften, Hanna S Hepp, Melissa Biemond, Ramon Arens.

  CD8+ T cells eliminate infected and malignant cells through coordinated proliferation and effector differentiation, processes supported by metabolic reprogramming that together form an interconnected, cross-regulated network. Emerging evidence indicates, however, that cell cycle progression and effector programming can be transiently uncoupled, with implications for T cell function and fate. Short-term modulation of cell cycle dynamics creates a window for metabolic rewiring, reshaping nutrient utilization, cytokine responsiveness, and bioenergetic capacity. This uncoupling can enhance T cell expansion, effector function, and antitumor activity. Collectively, these findings indicate that the cell cycle functions as an instructive checkpoint integrating metabolic and differentiation programs, not merely supporting proliferation. Understanding this interplay provides a conceptual framework to optimize T cell-based immunotherapies and rationally design chemoimmunotherapy combinations.

Keywords:  CD8(+) T cells; T cell differentiation; adoptive cell transfer; cell cycle progression; immunotherapy; metabolic reprogramming

DOI:  https://doi.org/10.1016/j.it.2026.09.001
Cell Rep. 2026 Sep 29. pii: S2211-1247(26)01149-6. [Epub ahead of print]45(10): 118070

Contextual control of CD8+ T cell priming by dendritic cell subsets in tumor and inflammatory microenvironments.

Victoria P Schuster, Naomi Berkowitz, Kasidy Brown, Catherine Rousculp, Valentina Laverde, Julia R Unsworth, Megan K Ruhland.

  Migratory and lymph node-resident dendritic cells occupy distinct niches and drive T cell activation during infection, vaccination, and cancer. How tissue context and dendritic cell subset-specific transcriptional programs integrate to shape CD8+ T cell priming remains incompletely defined. Using fluorescent antigen, we track antigen distribution, dendritic cell transcriptional programming, and cross-presentation across tumor, inflamed, and steady-state tissues. Tumor antigen is more widely distributed among lymph node dendritic cells than skin-derived antigen. Migratory type 1 dendritic cells display higher expression of cross-presentation machinery and superior per-cell cross-presentation and induction of CD8+ T cell proliferation compared to lymph node-resident type 1 dendritic cells. Ultimately, antigen access and cell-specific cross-presentation efficiency together predict the quality of CD8+ T cell priming. These results identify migratory type 1 dendritic cells as central mediators of antitumor CD8+ T cell responses and support therapeutic strategies that augment the efficiency of resident dendritic cell cross-presentation.

Keywords:  CP: cancer; CP: immunology; T cell priming; antigen transfer; antitumor immunity; cross-presentation; dendritic cells; lymph node; melanoma; tumor immunology

DOI:  https://doi.org/10.1016/j.celrep.2026.118070
Front Immunol. 2026 ;17 1963773

Immune remodeling of tumor-draining lymph nodes: mechanistic determinants of checkpoint blockade responsiveness.

Caiyan Jia, Shuxuan Li, Muhua Chen, Wuxia Yang, Yanqi Song, Aidi Wang, Baoshan Liu.

  Remodeling of tumor-draining lymph nodes (tdLNs) can precede overt nodal metastasis and has emerged as a determinant of immune checkpoint blockade (ICB) responsiveness. Sustained lymphatic delivery of tumor-derived antigens, extracellular vesicles, cytokines, and metabolites perturbs stromal and vascular programs, including lymphatic expansion, high endothelial venule dysfunction, and disruption of fibroblastic reticular cell (FRC) networks, with downstream impairment of antigen presentation and T-cell priming. Metabolites such as lactate and adenosine further promote tolerogenic antigen-presenting cell states and increase the activation requirements of tumor-reactive T cells. These changes are predicted to reduce the availability of TCF1+ progenitor-exhausted CD8+ T cells (Tpex), an ICB-responsive reservoir that sustains clonal expansion during PD-1/PD-L1 blockade. The Review links tdLN structural, cellular, and metabolic remodeling to ICB response and resistance, highlights reinforcement of regulatory circuits after metastatic colonization, and discusses translational strategies that incorporate tdLN functional state into therapeutic design, including restoration of type 1 conventional DC (cDC1) competence, metabolic co-targeting, neoadjuvant sequencing, adoptive use of tdLN-derived T cells, and biomarker-guided planning of local therapies.

Keywords:  TPEx; dendritic cell cross-presentation; immune checkpoint blockade; lymph node stromal remodeling; tumor-draining lymph nodes

DOI:  https://doi.org/10.3389/fimmu.2026.1963773
medRxiv. 2026 Sep 12. pii: 2026.08.18.26360744. [Epub ahead of print]

Macrophage-CD8⁺ T Cell Spatial Coupling Defines an Innate-Adaptive Injury Niche in Human Checkpoint Inhibitor Hepatotoxicity.

Jacob M Bogdanov, Neil Zhao, Helia Alavifard, David E Kleiner, Robert J Fontana, Andrew A Stolz, Akil Merchant, Jonathan Z Sexton, Lily Dara.

Background & Aims: Immune-mediated liver injury from immune checkpoint inhibitors (ILICI) is a major immune-related adverse event that limits cancer immunotherapy, yet its tissue-level immunobiology is poorly defined and its management is largely extrapolated from autoimmune hepatitis (AIH). We previously identified a tri-cellular CD8+ T cell-macrophage-hepatocyte injury niche in a murine model of ILICI; here, we tested whether this niche is recapitulated in human disease.
Methods: We applied imaging mass cytometry with a 32-marker panel to liver biopsies from patients with ILICI (n = 12), AIH as a disease comparator (n = 14), and healthy controls (n = 2), profiling approximately 297,000 single cells across 144 regions of interest with spatially resolved detection of apoptosis (cleaved caspase-3, cC3) and pyroptosis (cleaved gasdermin D, cGSDMD).
Results: We detected histiocyte-rich granulomas in ILICI consisting of macrophages and CD8+ T cells, including activated memory-effector subsets. Permutation-based spatial analysis identified CD8+ T cell-macrophage co-localization as the most frequent significant interaction in ILICI, organizing into integrated innate-adaptive cellular neighborhoods that concentrated cC3-and cGSDMD-positive cells. Descriptively, this contrasted with AIH, in which immune cells and stroma were more spatially compartmentalized. CD8+ T-cell and macrophage densities correlated with Ishak necroinflammation scores, jaundice, and granuloma formation.
Conclusions: These findings provide a single-cell spatial proteomic characterization of human ILICI in situ; they recapitulate the tri-cellular CD8-macrophage-hepatocyte niche we previously defined in a murine model and characterize ILICI as a spatially organized innate-adaptive inflammatory process, nominating myeloid signaling and CD8-macrophage interactions as candidate liver-directed targets to uncouple hepatotoxicity from anti-tumor immunity.
Impact and implications: This study provides a spatially resolved single-cell proteomic characterization of immune-mediated liver injury from checkpoint inhibitors (ILICI) in human tissue, revealing that macrophages and CD8⁺ T cells are not merely co-present but reproducibly co-localized into integrated inflammatory neighborhoods where apoptotic and pyroptotic cell death is concentrated. These findings are important for hepatologists and oncologists because they reframe ILICI as a spatially organized innate-adaptive process, distinct from autoimmune hepatitis, suggesting that current treatment strategies extrapolated from AIH may not optimally target the underlying pathobiology. Our results nominate myeloid signaling, inflammatory cell death pathways, and macrophage-CD8⁺ T cell interactions as candidate liver-directed therapeutic targets, offering a rationale for mechanism-based interventions that could uncouple hepatotoxicity from anti-tumor immunity and allow patients to remain on effective cancer immunotherapy.

DOI: https://doi.org/10.64898/2026.08.18.26360744