Mechanistic analysis on epigenetic programming of tumor drug resistance.

Drug resistance remains a critical clinical bottleneck restricting long-term curative efficacy of chemo-, targeted, and other therapies against human malignancies. Drug-tolerant persister (DTP) cancer cells and intratumoral heterogeneity substantially compromise therapeutic responses and worsen patient clinical prognosis. This review summarizes core epigenetic regulatory mechanisms of drug resistance, including DNA methylation, histone modifications, non-coding RNAs (ncRNAs), N⁶-methyladenosine (m⁶A) RNA methylation, and metabolism-epigenetic crosstalk axis, elaborating the mechanistic links between epigenetic programming and the acquisition of tumor drug resistance. The dynamic epigenetic alterations remodel aberrant transcriptional landscapes to empower cancer cells to circumvent cytotoxic drug elimination. Distinct from irreversible genomic mutations, epigenetic modifications are pharmacologically reversible; such biological plasticity enables combinatorial regimens pairing epigenetic modulators with conventional cytotoxic agents as a viable strategy to reverse therapeutic resistance. In-depth dissection of the epigenetic regulatory networks facilitates identification of novel epigenetic biomarkers and druggable targets, providing rationale for developing personalized combination therapies and ultimately improving clinical outcomes of drug-resistant cancer patients.