Sensory neurons encode long-term inflammatory memory that promotes gastric regeneration and tumorigenesis

SUMMARY Inflammatory memory has emerged as a fundamental principle by which prior injury shapes future tissue responses, yet whether sensory neurons participate in long-term tissue memory remains unknown. Here, we show that vagal sensory neurons acquire a durable, experience-dependent state following gastric injury or Helicobacter pylori infection, leading to enhanced regeneration, metaplasia, and tumor progression upon re-injury. This neuronal program is stable, functionally transferable, and sufficient to drive epithelial responses in vivo. Mechanistically, injury-activated ILC2s establish sensory neuronal memory through IL-13–dependent epigenetic remodeling, inducing SMYD4-mediated H3K4 trimethylation and promoting CGRP-dependent activation of gastric epithelial cells. Together, our findings support a model in which tissue memory is not restricted to epithelial or immune compartments but emerges through coordinated long-term adaptations across multiple cellular systems. Within this framework, sensory neurons provide a persistent substrate for recall responses, linking prior inflammatory experience to sustained epithelial plasticity and cancer susceptibility. HIGHLIGHTS Sensory neurons function as a durable compartment of tissue memory. CGRP–RAMP1 signaling couples neuronal memory to gastric stem cells. ILC2-derived IL-13 establishes sensory neuronal memory programs. SMYD4-mediated H3K4me3 stabilizes long-term neuronal memory. Neuronal memory promotes gastric regeneration and tumor susceptibility.