Abstract 4078: Vagal sensory neuronal inflammatory memory promotes gastric tumorigenesis through ILC2-mediated epigenetic signaling and the CGRP/Ramp1 axis

Abstract Background: Mammalian tissues can “remember” prior inflammatory or injurious events and respond more rapidly to later stimuli. Whether vagus-derived sensory neurons encode such experiences and convert them into tumor-promoting signals remains unknown. We show that inflammatory memory within vagal sensory neurons drives gastric regeneration and tumorigenesis through ILC2-mediated epigenetic reinforcement and CGRP/RAMP1 signaling. Methods: Gastric injury was induced by high-dose tamoxifen (HDT) or Helicobacter pylori infection/eradication. Orthotopic (ACKP) and spontaneous (Iqgap3-CreERT2; KRASG12D) tumor models assessed memory-driven initiation. Trpv1-Cre; hM3Dq and Trpv1-Cre; DTA mice enabled chemogenetic activation or ablation of nodose ganglion (NG) neurons. An AAV-C-Fos-tTA/TetO-Cre-DTA TRAP system labeled and ablated neurons activated during the first injury. Ramp1 was deleted in gastric stem cells (Iqgap3-CreERT2; Ramp1 flox), and IL25R+ ILC2s were depleted genetically or pharmacologically. Chromatin of sorted NG neurons was analyzed by ChIP-qPCR for H3K4me3 enrichment at memory loci. Results: Prior injury produced persistent “neuronal memory” marked by expanded CGRP+ fibers that accelerated mucosal recovery but enhanced metaplasia and tumorigenesis. Activation of Trpv1+ NG neurons was required; activation mimicked memory, while ablation or vagotomy abolished it. TRAP tracing showed reactivated neurons during reinjury overlapped with and exceeded those from the first; ablating the initial cohort erased the phenotype. MRI and c-Fos in the brainstem revealed stronger vagal signals after reinjury, indicating peripheral memory transmission to the central axis. During memory formation, subsets of sensory terminals directly innervated gastric isthmus stem cells; anterograde and retrograde tracing verified bidirectional connectivity, providing a structural basis for rapid signal recall. Memory neurons released CGRP acting on Ramp1+ isthmus stem cells; deleting or antagonizing Ramp1 suppressed dysplasia and tumorigenesis. IL25R+ ILC2s infiltrated the isthmus and maintained NG memory via IL-5-triggered CGRP release, Wnt5a-guided terminal attraction, and IL-13-induced SMYD4 with enhanced H3K4me3 in NG neurons. These cues reinforced the feedback sustaining the memory state. Conclusions: We identify a vagal sensory neuronal inflammatory memory circuit linking prior injury to gastric tumor initiation. ILC2-mediated IL-13/SMYD4/H3K4me3 signaling stabilizes memory within NG neurons, while CGRP/RAMP1 and neuro-epithelial contacts transmit it to the mucosa, forming a neuro-epigenetic feedback loop driving inflammation-associated gastric cancer. Citation Format: Yi Zeng, Puran Zhang, Ruhong Tu, Feijing Wu, Xiaofei Zhi, Jin Qian, Biyun Zheng, Hualong Zheng, Shuang Li, Hiroki Kobayashi, Yosuke Ochiai, Masahiro Hata, Juli Lin, Junya Arai, Leah B. Zamechek, Timothy C. Wang. Vagal sensory neuronal inflammatory memory promotes gastric tumorigenesis through ILC2-mediated epigenetic signaling and the CGRP/Ramp1 axis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4078.