Spatial remodeling of inflammatory niches drives stemness acquisition and malignant transformation during early gastric tumorigenesis.

BACKGROUND: Early gastric tumorigenesis is a multistep process characterized by progressive inflammatory remodeling of the gastric mucosa. This study aimed to identify how spatial organization of precancerous lesions contributes to stemness acquisition and malignant transformation during the earliest stages of gastric cancer (GC). METHODS: We profiled human gastric tissues spanning precancerous lesions to very early-stage GC using integrated single-cell and spatial transcriptomic analyses. By reconstructing spatially resolved cellular interactions across disease stages, we systematically delineated inflammation-associated niches that emerge prior to overt malignancy. Critical signaling pathways operative within these niches were further interrogated and functionally validated via colony and spheroid formation assays with AGS and MKN45 cells in vitro, as well as mouse xenograft models in vivo. RESULTS: Spatial transcriptomic analyses revealed the formation of discrete inflammatory niches within precancerous gastric mucosa, characterized by tightly coordinated interactions between epithelial and immune cell populations. These niches progressively supported epithelial stemness programs and preceded malignant transformation. Mechanistically, these spatially confined niches activated a stemness-associated transcriptional program in epithelial cells, thereby stabilizing early tumor-initiating states. Chemokine-mediated signaling within these niches orchestrated the regional recruitment and polarization of tumor-associated macrophages, reinforcing a self-sustaining inflammatory microenvironment. Therapeutic co-targeting of niche-associated chemokine signaling and macrophage survival pathways synergistically attenuated early tumorigenic potential in xenograft models. CONCLUSIONS: This study uncovers spatially organized inflammatory niches that precede and promote early gastric tumorigenesis. By linking precancerous inflammation to stemness acquisition through spatial microenvironmental remodeling, these findings highlight a critical, targetable window for early intervention in GC.