Molecular reprogramming in cutaneous melanoma: the central role of G9a and EZH2 methyltransferase inhibitors in tumor plasticity, immune evasion, and therapeutic resistance

Cutaneous melanoma remains a leading cause of skin cancer-related mortality despite significant therapeutic advances, with treatment resistance and immune evasion representing major clinical challenges. Epigenetic dysregulation, particularly through the histone methyltransferases G9a (EHMT2) and Enhancer of Zeste Homolog 2 (EZH2), plays a pivotal role in melanoma progression, therapeutic resistance, and immune escape. G9a catalyzes the deposition of H3K9me2, whereas EZH2, the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), mediates H3K27me3 deposition, thereby establishing repressive chromatin states that silence tumor suppressor genes and immune-related pathways. These enzymes are frequently overexpressed in melanoma and cooperate to maintain dedifferentiated and invasive tumor phenotypes characterized by enhanced plasticity and reduced immunogenicity. Acral melanoma, a distinct subtype with a low ultraviolet (UV) mutational burden, appears to be particularly dependent on epigenetic reprogramming and exhibits an immunologically “cold” tumor microenvironment that is associated with poor responses to current therapies. Preclinical studies demonstrate that pharmacological inhibition of G9a with compounds such as UNC0642 and EZH2 with agents including tazemetostat can restore the expression of silenced genes, enhance antigen presentation, and improve tumor immunogenicity. Importantly, the functional crosstalk between G9a and EZH2 creates redundant repressive mechanisms that may limit the efficacy of single-agent therapies supporting the development of combination strategies targeting both pathways. Dual inhibition has shown promise in pre-clinical models by converting immune-excluded “cold” tumors into immune-responsive “hot” tumors that are more susceptible to checkpoint blockade and adoptive cell therapies. While EZH2 inhibitors have progressed to clinical trials in various solid tumors, melanoma-specific studies remain limited despite strong biological rationale. This review synthesizes the current understanding of G9a and EZH2 biology in melanoma, evaluates therapeutic targeting strategies, and highlights the potential for epigenetic reprogramming to overcome treatment resistance and enhance immunotherapy responses in this aggressive malignancy.