The role and clinical impact of aberrant m6A RNA modification in cancer

Abstract

N6-methyladenosine (m6A) constitutes the most prevalent internal modification of eukaryotic mRNAs, conferring dynamic, sequence-independent regulation of gene expression through a reversible epitranscriptomic mechanism. Orchestrated by methyltransferase (“writers”), demethylases (“erasers”), and binding proteins (“readers”), m6A governs critical nodes of RNA metabolism, including splicing, nuclear export, transcript stability, and translational control. In this review, we systematically dissect how dysregulated m6A methylation fuels malignant transformation and progression by reinforcing core oncogenic hallmarks, sustained proliferation, metastasis, metabolic rewiring, and resistance to programmed cell death. Beyond cancer cell-intrinsic effects, m6A modification profoundly remodels the tumor immune microenvironment through coordinated regulation of immune cell function and immune checkpoint molecules, thereby facilitating immune evasion. We further discuss the context-dependent oncogenic or tumor-suppressive roles of specific m6A regulators and their impact on therapeutic resistance. Finally, we evaluate the translational potential of targeting the m6A axis, highlighting recent advances in small-molecule inhibitors and combination immunotherapies. Overcoming delivery challenges remains essential for integrating m6A-targeted strategies into clinical practice and advancing personalized oncology.