Epigenetic regulation of cuproptosis in cancer: mechanisms, microenvironment, and therapeutic implications

Cuproptosis is a regulated form of cell death triggered by copper overload and dependent on mitochondrial metabolism, particularly through FDX1-mediated protein lipoylation and TCA cycle disruption. Recent studies have revealed that epigenetic mechanisms, including DNA methylation, histone modifications, non-coding RNAs, and RNA chemical modifications such as m⁶A and lactylation, critically regulate the expression of copper transporters, lipoylation enzymes, mitochondrial metabolic proteins, and stress response pathways, thereby modulating tumor cell susceptibility or resistance to cuproptosis. For example, DNA methylation can control copper homeostasis genes through a DNMT/miRNA/copper transporter axis, while histone lactylation links metabolic rewiring to copper accumulation. Non-coding RNAs and RNA modifications fine-tune the transcription and translation of key cuproptosis regulators, providing dynamic control over cell fate. The tumor microenvironment (TME) further influences cuproptosis by shaping copper availability, redox status, hypoxia, and metabolic reprogramming, and interacts with immune surveillance and PD-1/PD-L1 signaling. Translationally, copper ionophores, nanomedicine-based delivery systems, and combination strategies targeting both metabolic vulnerabilities and the TME offer promising approaches to induce tumor-specific cuproptosis while minimizing toxicity. Overall, the integration of molecular, epigenetic, and microenvironmental regulation in cuproptosis provides new insights into tumor metabolic vulnerabilities and offers potential targets for precision anticancer therapies.