NSD proteins in anti-tumor immunity and their therapeutic targeting by protein degraders.

Abstract

Chromatin modifiers, owing to their enzymatic activities and frequent overexpression or hyperactivation in cancer, have emerged as promising therapeutic targets. Among these, the nuclear receptor-binding SET domain (NSD) family of proteins catalyzes lysine methylation-a key histone post-translational modification that is implicated in diverse biological processes, primarily through the regulation of transcription. Previous studies have demonstrated that NSD proteins are often overexpressed, mutated, or involved in chromosomal translocations in both hematologic malignancies and solid tumors, thereby regulating tumor initiation and progression. Motivated by these insights, a range of NSD-targeting agents, including targeted protein degraders such as proteolysis-targeting chimeras (PROTACs), have been developed and have exhibited notable anti-cancer activities. In this review, we provide an overview of the NSD family of protein, highlighting their roles in regulating anti-tumor immunity and their implications for immunotherapy response and resistance. We further assess the current landscape of NSD-targeted protein degrader-based therapeutics and their potential utility as anti-cancer agents.