Chromatin accessibility trajectories reveal pre-cancerous epigenetic priming and an acid-driven immunotherapy-resistant gastric cancer subtype.

Chromatin remodeling is prominent in cancers, yet it remains obscure how chromatin dynamics underlies stepwise tumorigenesis and informs anti-cancer therapeutics. By decoding a large-scale chromatin accessibility atlas of 650 multistage samples from 439 patients, we delineate epigenetic switches spanning multistep gastric tumorigenesis. A cancer-resembling epigenetic priming state in intestinal metaplasia licenses subsequent tumor initiation. In advanced malignancies, inter-tumoral diversity stratifies three epigenomic subtypes. The proliferative and mesenchymal-inflammatory subtypes are sensitive to neoadjuvant immunotherapy, while the pseudo-gastric subtype is intrinsically drug resistant. Mechanistically, the refractory subtype is featured by a unique gastric lineage-mimicking phenotype, governed in part by FOSL2 to up-regulate H+/K+ ATPase transporters and sculpt an acidic milieu suppressing CD8+ T cells. Inhibition of this phenotype by either FOSL2 depletion or vonoprazan, a clinically available acid blocker, sensitizes immunotherapy. Collectively, these findings highlight that chromatin accessibility dynamics facilitates sequential tumorigenesis from gastric pre-cancer and defines subtypes exploitable to guide immunotherapy and overcome drug resistance.