METTL3 in esophageal cancer: Current insights into molecular mechanisms, subtype heterogeneity and targeted therapy...

Esophageal cancer (EC), comprising esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), urgently requires novel targeted therapies. The m⁶A methyltransferase METTL3 has emerged as a critical epitranscriptomic regulator in gastrointestinal malignancies. In ESCC, METTL3 functions predominantly as an oncogene, driving tumor progression via m⁶A‑dependent modulation of RNA stability, splicing, and translation across key networks, including NOTCH1, EGR1/Snail and Wnt/β‑catenin. Conversely, hypotheses regarding m⁶A‑independent functions or direct immune‑checkpoint regulation remain unvalidated in EC. Crucially, METTL3 actively modulates DNA damage repair and radiotherapy resistance, exposing a promising therapeutic vulnerability, although clinical pharmacological development remains nascent. Furthermore, METTL3 biology in EAC remains conspicuously uncharacterized. By strictly stratifying evidence by EC subtype, the present review distinguishes empirically validated mechanisms from premature cross‑cancer extrapolations. Ultimately, a novel conceptual framework that redefines METTL3 not merely as a static oncogene, but as a dynamic, context‑dependent regulatory hub, is proposed. Under therapeutic stress, METTL3 amplifies cellular phenotypic plasticity, systematically orchestrating tumor adaptation and treatment resistance.