Esophageal cancer is a significant global health concern, with esophageal squamous cell carcinoma being the predominant subtype in high-incidence regions like China. Despite advances in multidisciplinary treatments, the prognosis for ESCC remains poor, with systemic chemotherapy facing the challenge of drug resistance. Epigenetic alterations, particularly DNA methylation, play a crucial role in ESCC carcinogenesis and therapeutic response. Aberrant DNA methylations, including global hypomethylation and promoter-specific hyper-methylation, disrupt critical pathways such as cell cycle regulation, apoptosis, and DNA repair, contributing to chemoresistance. Several studies have identified methylation markers that predict treatment response, particularly for chemotherapy, targeted therapy and immunotherapy, such as