EZH2, a prominent orchestrator of genetic and epigenetic regulation of solid tumor microenvironment and immunotherapy

Immune checkpoint blockade (ICB) is regarded as a promising strategy for cancer therapy. The histone methyltransferase, Enhancer of Zeste Homolog 2 (EZH2), has been implicated in the carcinogenesis of numerous solid tumors. However, the underlying mechanism of EZH2 in cancer immunotherapeutic resistance remains unknown. EZH2 orchestrates the regulation of the innate and adaptive immune systems of the tumor microenvironment (TME). Profound epigenetic and transcriptomic changes induced by EZH2 in tumor cells and immune cells mobilize the elements of the TME, leading to immune-suppressive activity of solid tumors. In this review, we summarized the dynamic functions of EZH2 on the different components of the TME, including tumor cells, T cells, macrophages, natural killer cells, myeloid-derived suppressor cells, dendritic cells, fibroblasts, and mesenchymal stem cells. Several ongoing anti-tumor clinical trials using EZH2 inhibitors have also been included as translational perspectives. In conclusion, based combinational therapy to enable ICB could offer a survival benefit in patients with cancer.