The mechanisms of therapeutic resistance of m6A modification in gastrointestinal cancers

Drug resistance in gastrointestinal (GI) cancers, including gastric, colorectal, hepatocellular, and pancreatic carcinomas, represents a major obstacle to effective therapeutic intervention. A key contributor to this resistance is the dysregulation of RNA N6-methyladenosine (m6A) modification. Regulated by methyltransferases ("writers"), demethylases ("erasers"), and binding proteins ("readers"), m6A modifications play a crucial role in modulating RNA stability, translation, and degradation. Altered m6A levels and dysfunction of associated regulatory proteins perturb essential biological processes such as gene expression, metabolic reprogramming, DNA damage repair, cancer stem cell maintenance, and immune evasion. These disruptions collectively promote resistance to chemotherapy, targeted therapy, and immunotherapy across various GI malignancies. Therefore, targeting the m6A modification machinery—including writers, erasers, and readers—may offer a therapeutic entry point, although most strategies remain preclinical and require rigorous validation before clinical implementation. This review summarizes current findings on the mechanisms by which dysregulated m6A modifications drive therapeutic resistance in GI cancers and discusses emerging approaches aimed at targeting this pathway to overcome drug resistance.