Cancer immunology, immunotherapy : CII · 2025
Spatially resolved endothelial signaling via nampt-itga5 drives immune evasion in stem-like gastric cancer.
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Sung Ji-Yong, Cheong Jae-Ho, Kim Eui Tae
Аннотация
BACKGROUND: Stem-like gastric cancer (GC) is an aggressive molecular subtype marked by poor prognosis and limited response to immune checkpoint blockade (ICB). The spatial mechanisms driving this resistance remain unclear.
METHODS: We conducted spatially resolved single-cell transcriptomic profiling of diffuse-type GC tissues to uncover the spatial architecture and functional diversity of tumor and stromal populations. Cellular heterogeneity and region-specific signaling pathways were characterized using integrative bioinformatics analyses.
RESULTS: We identified transcriptionally diverse, high-entropy cell populations predominantly localized in the deep tumor regions. These included unique endothelial and fibroblast subsets enriched for pro-tumorigenic and immune-regulatory signaling. A notable finding was the engagement of deep-region endothelial cells in VISFATIN (extracellular NAMPT) signaling through the ITGA5-ITGB1 integrin axis, associated with immune evasion and poor prognosis. This endothelial signaling program is distinct from and functionally independent of cancer-associated fibroblast (CAF)-mediated pathways. Elevated expression of the NAMPT-ITGA5-ITGB1 axis was observed in ICB non-responders and correlated with reduced overall survival.
CONCLUSIONS: Our study delineates spatially defined cellular programs that contribute to immune escape in stem-like GC, highlighting a novel VISFATIN-integrin signaling axis as a potential biomarker and therapeutic target in immunotherapy-resistant tumors.
METHODS: We conducted spatially resolved single-cell transcriptomic profiling of diffuse-type GC tissues to uncover the spatial architecture and functional diversity of tumor and stromal populations. Cellular heterogeneity and region-specific signaling pathways were characterized using integrative bioinformatics analyses.
RESULTS: We identified transcriptionally diverse, high-entropy cell populations predominantly localized in the deep tumor regions. These included unique endothelial and fibroblast subsets enriched for pro-tumorigenic and immune-regulatory signaling. A notable finding was the engagement of deep-region endothelial cells in VISFATIN (extracellular NAMPT) signaling through the ITGA5-ITGB1 integrin axis, associated with immune evasion and poor prognosis. This endothelial signaling program is distinct from and functionally independent of cancer-associated fibroblast (CAF)-mediated pathways. Elevated expression of the NAMPT-ITGA5-ITGB1 axis was observed in ICB non-responders and correlated with reduced overall survival.
CONCLUSIONS: Our study delineates spatially defined cellular programs that contribute to immune escape in stem-like GC, highlighting a novel VISFATIN-integrin signaling axis as a potential biomarker and therapeutic target in immunotherapy-resistant tumors.