Helicobacter pylori-Induced Inflammatory Cancer Transformation Microenvironment Drives Gastric Carcinogenesis
Yufei Fu1, Jiajing Tong2, Manxuan Zhu1
1Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China.
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:
H pylori infection profoundly alters the ICTM within immune and stromal cells during and after eradication. Following eradication, epithelial cells exhibit distinct trajectories after eradication, with the pathological improvement group showing increased MUC5AC expression and the non-improvement group displaying a malignant trajectory. Immunomodulatory CAFs (iCAFs) critically promote epithelial malignancy and immunosuppression. CCN2+ iCAF1 and C3+ 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.
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