The Lactate–Lactylation Axis as a Metabolic–Epigenetic Framework for Therapeutic Adaptation in Esophageal Squamous Cell Carcinoma

Abstract

Simple Summary Esophageal squamous cell carcinoma is an aggressive cancer in which treatment failure can reflect adaptation by tumor cells and the surrounding immune environment to chemotherapy and immunotherapy. Lactate, traditionally viewed as a glycolytic byproduct, can also influence gene expression and protein function through lysine lactylation. This review examines how the lactate–lactylation axis may contribute to therapeutic adaptation in esophageal squamous cell carcinoma. We distinguish evidence linking lactate metabolism to treatment outcomes from evidence showing lactylation-associated changes and from stronger studies that directly test a defined lactylation site. Specific lactylation events have been linked to DNA repair, regulated cell death, and immune evasion, although clinical validation remains limited. The review highlights the need for reliable site-specific measurements and prospective patient studies before these mechanisms can guide treatment selection or new therapies.