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

A pseudo-gastric epigenomic subtype in gastric cancer is intrinsically drug resistant and characterized by an acid-driven immunotherapy resistance linked to FOSL2 activity.

• Why it matters: Understanding how chromatin dynamics influence tumor progression and therapeutic response can improve strategies for treating gastric cancer, especially resistant subtypes.
• What they did: Decoding chromatin accessibility in 650 samples from 439 patients revealed three epigenomic subtypes, with the resistant subtype showing a gastric lineage-mimicking phenotype regulated by FOSL2.
• The result: Targeting FOSL2 or acid production with vonoprazan sensitizes this subtype to immunotherapy, suggesting new avenues to overcome drug resistance in gastric cancer.