Targeting m6A RNA methylation to sensitize cancer cells to DNA-damaging therapies

Abstract N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic mRNA and plays a crucial role in post-transcriptional gene regulation. Recent studies have revealed that m6A modification is dysregulated in various cancers, influencing tumor initiation, progression, and metastasis. This review highlights the role of m6A in modulating cancer cell responses to DNA-damaging therapies, including its effects on DNA repair, apoptosis, cell cycle control, and immune signaling. We discuss specific examples where targeting m6A-regulators enhances the sensitivity of cancer cells to DNA-damaging agents. Importantly, such strategies may be particularly valuable for older patients, in whom DNA-damaging therapies are often poorly tolerated due to frailty and comorbidities. By integrating mechanistic insights with translational potential, this review provides a roadmap for exploiting the m6A epitranscriptome to enhance cancer treatment outcomes.