Epigenetic dysregulation and microenvironment remodeling in pancreatic cancer.

Epigenetic dysregulation including frequent mutations in epigenetic regulators alongside nonmutational reprogramming driven by oncogenic and metabolic stresses represents a hallmark of pancreatic ductal adenocarcinoma (PDAC). Recent advances using low-input epigenomics and single-cell technologies have revealed their role in fostering cellular plasticity, stromal reprogramming, immune evasion, and therapy resistance. This review synthesizes current knowledge of epigenetic mechanisms in PDAC pathogenesis, highlighting their stage- and context-dependent roles in tumor progression, tumor microenvironment crosstalk, and metabolic adaptation. We further highlight emerging therapeutic strategies that target epigenetic vulnerabilities. By integrating cutting-edge epigenomic profiling with functional studies, we outline a roadmap for translating epigenetic discoveries into clinical strategies against this lethal malignancy.