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METTL3 in esophageal cancer: Current insights into molecular mechanisms, subtype heterogeneity and targeted therapy prospects (Review)

Year: 2026
Type: article
Abstract: Esophageal cancer (EC), comprising esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), urgently requires novel targeted therapies.The m 6 A methyltransferase METTL3 has emerged as a critical epitranscriptomic regulator in gastrointestinal malignancies.In ESCC, METTL3 functions predominantly as an oncogene, driving tumor progression via m 6 A-dependent modulation of RNA stability, splicing, and translation across key networks, including NOTCH1, EGR1/Snail and Wnt/β-catenin.Conversely, hypotheses regarding m 6 A-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.Contents 1. Introduction 2. METTL3 expression and clinical significance in EC 3. METTL3-mediated regulatory mechanisms 4. METTL3-driven malignant phenotypes in ESCC 5. Therapeutic targeting of METTL3 in EC 6. Rationale against the extrapolation of ESCC-derived METTL3 biology to EAC 7. Challenges and future directions 8.
DOI: 10.3892/ijo.2026.5884
Language: English
Open Access status: hybrid
OpenAlex ID: W7155106633
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