Spatiotemporal multi-omics analysis uncovers NAD-dependent immunosuppressive niche triggering early gastric cancer

EGFR/ERBB2 signaling, fostering cancer initiation. We established gastric precancerous cell lines and organoids to demonstrate that NAMPT and AREG promote cellular proliferation in vitro. Furthermore, in the transgenic CEA-SV40 mouse model, targeting AREG and/or NAMPT disrupted key cell interactions, inhibited the JAK-STAT, MAPK, and NFκB pathways, and reduced PD-L1 expression, which was also confirmed by western blot in vitro. These interventions delayed disease progression, reversed the immunosuppressive microenvironment, and prevented malignant transformation. Clinical validation was conducted using endoscopically resected EGC specimens. Our study provides a precise spatiotemporal depiction of EGC development and identifies novel diagnostic markers and therapeutic targets for early intervention.