Lactylation Modification and Esophageal Cancer: Research Progress From Hypoxia‐Induced Metabolic Reprogramming to Immune Escape

Esophageal cancer is a common malignancy of the digestive tract, marked by aggressive invasion, unfavorable prognosis, and limited responsiveness to existing therapeutic strategies. Hypoxia-driven metabolic remodeling represents a key feature of the esophageal cancer microenvironment. In this context, enhanced glycolytic activity leads to lactate accumulation, thereby providing the metabolic substrate for lactylation. Lactylation, a recently recognized lysine post-translational modification, has been detected on both histone and non-histone proteins and regulates tumor biology by modulating chromatin accessibility, gene transcription, protein stability, and signaling pathway activity. Emerging evidence suggests that lactylation is closely involved in the malignant progression of esophageal cancer, including tumor cell proliferation, invasion, stemness maintenance, regulation of programmed cell death, immune escape, and treatment resistance. Under hypoxic conditions, increased lactate production may drive histone lactylation, including histone lactylation marks such as H3K9la, H3K18la, and H4K12la, as well as lactylation of non-histone proteins. These modifications contribute to remodeling of the immunosuppressive tumor microenvironment and weaken anti-tumor immune responses. This review highlights the biological basis of lactate metabolism and lactylation, focusing on their roles in metabolic reprogramming driven by hypoxia, the advancement of tumors, the regulation of the immune microenvironment, immune evasion, and resistance to therapy in esophageal cancer. Additionally, we explore the potential clinical significance of molecules associated with lactylation as diagnostic markers and therapeutic targets, offering fresh insights for precision treatment strategies in esophageal cancer.