DNA methyltransferase inhibitors in oncology: clinical progress, limitations and future directions.

Over the past century, cancer therapy has evolved from broadly cytotoxic approaches to mechanism-based treatments. Recognition of epigenetic dysregulation as a cancer hallmark paved the way for epigenetic therapies. The earliest to gain U.S. Food and Drug Administration (FDA) approval were DNA methyltransferase inhibitors (DNMTis), such as azacitidine and decitabine, which remain cornerstone agents in epigenetic therapy. By reversing aberrant DNA hypermethylation, DNMTis restore silenced tumor suppressor pathways, induce cellular differentiation, trigger DNA-damage-driven apoptosis, and enhance tumor immunogenicity. Although DNMTi monotherapy shows limited efficacy particularly in solid tumors, DNMTis can potentiate immunotherapy, chemotherapy or targeted agents in optimized combinatorial modalities to produce antitumor responses and overcome therapeutic resistance. For instance, combining DNMTis with the BCL-2 inhibitor venetoclax has produced substantial clinical benefit in hematologic malignancies and is now an FDA-approved standard-of-care regimen. Emerging dual-epigenetic strategies, including DNMTi and histone deacetylase inhibitors (HDACi), further expand therapeutic potential particularly in hormone-negative cancers. A deeper mechanistic understanding of standard DNMTis, together with further refinement of next-generation DNMTis beyond pharmacokinetic improvements, is essential to achieve more durable anti-cancer responses. Future efforts should prioritize optimized dosing and combinatorial regimens, alongside biomarker-guided patient selection and more targeted epigenetic approaches to improve efficacy, especially in solid tumors.