Spatially resolved endothelial signaling via nampt-itga5 drives immune evasion in stem-like gastric cancer

Abstract

BackgroundStem-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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.