Yufei Fu, Jing Tong, Manxuan Zhu, Liuyi Xu, Fengming Huang, Yixin Zhang, Xinyue Wang, Zhejiong Wang, Jingcheng Zhang, Jinjing Lv, Tao Jiang, Bin Lv, Guangji Zhang
BACKGROUND & AIMS: Helicobacter pylori (H pylori) eradication significantly reduces gastric cancer risk but offers limited benefit for patients with advanced atrophic gastritis. After eradication, a persistent inflammatory-cancer-transformation microenvironment (ICTM) drives gastric carcinogenesis, warranting further investigation. METHODS: We constructed a single-cell atlas of 22 gastric antral mucosae across disease stages, including normal controls, H pylori-infected non-atrophic gastritis, H pylori-infected chronic atrophic gastritis, and post-eradication chronic atrophic gastritis (stratified by pathological improvement). Key findings were validated via multiplex immunofluorescence and primary cancer-associated fibroblast (CAF) experiments. RESULTS: iCAF3 are enriched in infected tissues and persist in post-eradication patients with CAG. H pylori infection reprograms iCAFs, leading to extracellular matrix reorganization and senescence with senescence-associated secretory phenotype. This reprogramming promotes epithelial malignant transformation and stemness. Infection-driven reprogramming of the iCAF-epithelial niche is accompanied by an immunosuppressive state after eradication. CONCLUSIONS: H pylori infection induces persistent ICTM after eradication. Infection-driven iCAF differentiation contributes to epithelial malignant transformation and a potential immunosuppressive microenvironment, linking to gastric carcinogenesis. Our findings underscore the critical role of ICTM transformation, highlighting the need to improve ICTM for post-H pylori eradication therapies, and indicate that specific iCAF subtypes represent promising intervention targets.