Aberrant DNA Methylation in Esophageal Squamous Cell Carcinoma and its Clinical Implications in Systemic Chemotherapy

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 p16 and GPX3 for cisplatin, MTHFR for 5-FU, CHFR for paclitaxel. DNA methyltransferase inhibitors and other epigenetic therapies are being explored to reverse these methylation changes and enhance therapeutic efficacy. However, the clinical utility of these markers remains limited due to the lack of large-scale validation and concerns over off-target effects. This review aims to summarize all aberrant methylation alterations in ESCC and the clinical implications of aberrantly methylated candidate genes identified in ESCC systemic chemotherapy, with the goal of further understanding the underlying molecular mechanisms, refining methylation-targeting therapies, and integrating them with conventional treatments to improve patient outcomes.