The m6A epitranscriptome in cancer therapy resistance: From cellular plasticity and metabolic rewiring to immune...

Cancer therapy resistance remains a major barrier to durable clinical benefit across chemotherapy, targeted therapy, cell-cycle-directed therapy, and immunotherapy. Although genetic alterations and epigenetic rewiring have long been recognized as major contributors to treatment failure, increasing evidence indicates that post-transcriptional regulation by the epitranscriptome represents an additional and highly dynamic layer of adaptive resistance. Among RNA modifications, N6-methyladenosine (m6A) has emerged as the most abundant internal modification in eukaryotic mRNA and a pivotal regulator of cancer progression, immune remodeling, and therapeutic response. Accumulating studies show that dysregulated m6A writers, erasers, and readers promote resistance by sustaining cellular plasticity and stemness, rewiring glucose and amino acid metabolism, reinforcing redox buffering and ferroptosis suppression, reshaping autophagy and mitochondrial homeostasis, and enhancing DNA damage repair and RNA processing programs. Beyond tumor-intrinsic survival, m6A also modulates immune escape by altering checkpoint responsiveness, immunometabolic suppression, and tumor-microenvironment communication. Recent advances have further expanded the conceptual framework of the field, revealing noncanonical functions of m6A regulators in adaptive translation, biomolecular condensate formation, and crosstalk with post-translational modifications such as lactylation. These findings position the m6A epitranscriptome not merely as a regulator of RNA fate, but as a systems-level coordinator of therapy-adaptive tumor states. In this review, we summarize current progress in understanding how m6A drives cancer therapy resistance across distinct therapeutic contexts, highlight emerging mechanistic frontiers, and discuss the translational potential and current challenges of targeting m6A regulators for overcoming resistant disease.