Unraveling the dual role of METTL3-mediated m6A RNA modification in bladder cancer: mechanisms, therapeutic vulnerabilities, and clinical implications

Abstract

Bladder cancer (BC) remains challenging due to its recurrence and metastasis, with METTL3-mediated m⁶ A RNA modification emerging as a key oncogenic driver. This review synthesizes METTL3's roles in BC progression, including tumor initiation, metastasis, stemness, and therapy resistance. We detail its regulation of critical pathways (e.g. HIF1A/IGF2BP3/BIRC5, AFF4/NF-κB/c-MYC) and dual functions in RNA stability and epigenetic crosstalk with DNA methylation. METTL3 promotes chemoresistance (e.g. circ0008399/WTAP/TNFAIP3) and immune evasion (PD-L1 stabilization), while its overexpression correlates with poor prognosis and cisplatin resistance. By integrating METTL3's interactions with m⁶ A readers (YTHDF1/2, IGF2BP3) and erasers (ALKBH5), we propose targeting METTL3 as a strategy to enhance chemotherapy and immunotherapy efficacy. This work underscores METTL3's potential as a diagnostic biomarker and therapeutic target, advancing precision oncology in BC.

Keywords: Bladder cancer; METTL3; RNA m6A modification; chemoresistance; epitranscriptomics; immune evasion; therapeutic targeting.