Recent update on the development of EZH2 inhibitors and degraders for cancer therapy.

Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), plays a pivotal role in epigenetic regulation by catalyzing the trimethylation of histone H3 at lysine 27 (H3K27me3), leading to transcriptional repression of target genes. Dysregulation of EZH2 has been implicated in various cancers, including lymphomas, prostate, and breast cancers, by promoting oncogenic transformation and tumor progression. Targeting EZH2 has been regarded as a promising strategy for cancer therapy. Over the past decade, significant progress has been made in the development of EZH2 inhibitors and degraders, several of which have been approved or are undergoing various clinical trials. These agents function by competing with the cofactor S-adenosyl-l-methionine (SAM) at the active site within the SET domain of EZH2, thereby preventing the methylation of H3K27 and reactivating silenced tumor suppressor genes. In addition, next-generation strategies, including dual EZH1/EZH2 inhibitors, PROTAC-based degraders, and combination regimens with immunotherapy or hormonal therapy, are being actively explored to enhance therapeutic benefit and overcome resistance mechanisms that limit monotherapy efficacy. This review provides an overview of the current landscape of EZH2-targeted therapies since 2020 and future directions for optimizing their application.