Metal-Based Epigenetic Therapeutics in Cancer: Mechanisms, Targets, and Opportunities for Overcoming Drug Resistance.

Epigenetic dysregulation is a hallmark of cancer and contributes to tumor initiation, progression, metastasis, and therapeutic resistance. Consequently, epigenetic drugs (epidrugs) targeting DNA methylation, histone modifications, and chromatin-associated proteins have emerged as an important class of anticancer agents. Approved therapies such as DNA methyltransferase inhibitors (DNMTis) and histone deacetylase inhibitors (HDACis) have demonstrated clinical benefit, particularly in hematological malignancies; however, their efficacy is often limited by off-target toxicity, acquired resistance, and incomplete target selectivity. In recent years, metallorganic compounds have gained attention as a novel generation of epigenetic modulators. The incorporation of metal centers provides unique structural, redox, and coordination properties that enable interactions with multiple epigenetic targets and facilitate the design of multifunctional agents. This review summarizes the major classes of epidrugs and discusses emerging metallorganic epigenetic therapeutics based on ruthenium, platinum, tin, copper, iridium, iron, technetium, rhenium, and gold. We examine their mechanisms of action against key epigenetic regulators, including DNMTs, HDACs, histone methyltransferases, bromodomain proteins, and chromatin-associated complexes. Particular attention is given to the potential of metal-based epidrugs to overcome therapeutic resistance through multimodal mechanisms that combine epigenetic reprogramming with modulation of DNA damage responses, oxidative stress, protein homeostasis, and chromatin organization. Although most metallorganic epidrugs remain in preclinical development, accumulating evidence suggests that they may offer advantages over conventional organic epigenetic inhibitors by enabling multi-target engagement and more durable antitumor responses. Together, these findings highlight the growing potential of metal-based epigenetic therapies and support their further development as innovative strategies for precision oncology.