Epigenetic regulation of EZH2 by ncRNAs: mechanisms and oncogenic implications

Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and core component of the polycomb repressive complex 2 (PRC2), is an important player in cancer progression through its powerful effects on chromatin remodeling and gene silencing. In addition to its classical role in regulating the cell cycle and tumor proliferation, numerous publications have identified the broad role of EZH2 in modulating the tumor immune microenvironment (TIME), leading to immune evasion and resistance to immunotherapy. EZH2 has been shown to silence immune surveillance genes by binding to H3K27me3 histone, leading to epigenetic silencing in lymphomas and thereby reducing tumor immunogenicity, which facilitates immune escape. EZH2 also modulates the recruitment and activity of immunosuppressive cells by epigenetically modifying cytokine and chemokine networks. Importantly, EZH2 upregulates PD-L1 expression either directly or indirectly through its pro-oncogenic activation of STAT3 signaling, which induces T cell exhaustion and ultimately resistance to checkpoint inhibitors in cancers such as breast cancer and glioblastoma. Furthermore, EZH2 also influences the regulation of immune-related microRNAs, including the suppression of the miR-144/451a cluster, which encourages immunosuppressive macrophage polarization. Pharmacological EZH2 inhibition has been shown to be an arm of a synergistic therapy, combining immune checkpoint blockade therapies, which can reinstate antigen presentation and T cell infiltration, highlighting EZH2 as an essential epigenetic modulator of tumor–immune interactions. It remains a viable target for therapy to overcome immune resistance and improve cancer immunotherapy outcomes.