Epigenetic regulation in cancer chemoresistance and combined therapeutic strategies

Chemotherapy remains a cornerstone treatment for various malignancies; however, its efficacy is often limited by the development of drug resistance, which increases the risk of tumor recurrence and metastasis. Chemoresistance arises from multiple mechanisms, including enhanced drug efflux, apoptosis inhibition, increased DNA damage repair, and the maintenance of cancer stem cells (CSCs). Recent studies have revealed that epigenetic alterations play a critical role in chemoresistance. DNA methylation, histone modifications, and non-coding RNAs contribute to resistance by regulating gene expression, signaling pathways, and CSC properties. RNA epigenetic modifications, such as N6-methyladenosine (m 6 A), N4-acetylcytidine (ac 4 C), and 5-methylcytidine (m 5 C), regulate mRNA stability, splicing, and translation efficiency, thereby sustaining CSC self-renewal and promoting resistance. Epigenetic-targeted agents, including DNA methyltransferase inhibitors (DNMTi), histone deacetylase inhibitors (HDACi), and emerging inhibitors targeting RNA-modifying enzymes, have demonstrated the potential to reverse resistance, suppress CSC traits, and enhance chemosensitivity in vitro and in vivo . Combining epigenetic drugs with conventional chemotherapy enables multi-level intervention in resistance mechanisms, significantly improving therapeutic outcomes and offering new avenues for personalized cancer treatment. Future studies should focus on developing precise biomarkers, optimizing combination strategies, and conducting clinical validation to advance the application of epigenetic interventions in chemoresistant cancers.