NUCLEAR RECEPTOR BINDING SET DOMAIN PROTEINS: ORCHESTRATING ANTI-TUMOR IMMUNITY AND THE PROMISE OF TARGETED DEGRADATION THERAPIES

• Dr. Eleni S. Konstantinou

  Department of Biological Applications and Technology, University of Ioannina, Greece

  Author

• Dr. Satoshi N. Fujimoto

  Department of Biophysics and Biochemistry, University of Tokyo, Japan

  Author

Nuclear Receptor Binding SET Domain (NSD) proteins, including NSD1, NSD2, and NSD3, are a family of histone lysine methyltransferases primarily responsible for H3K36 methylation. Their dysregulation is a common feature in various cancers, driving oncogenesis through aberrant gene expression. Beyond their direct roles in cell proliferation, emerging evidence highlights their critical, yet complex, involvement in modulating anti-tumor immunity and contributing to immune evasion. This article reviews the current understanding of how NSD proteins influence the tumor microenvironment, immune cell infiltration, and antigen presentation pathways. Specifically, NSD1 inactivation has been linked to "immune cold" phenotypes, NSD2 impacts MHC-I antigen presentation and immune cell differentiation, and NSD3 influences CD8+ T cell infiltration. Given their pivotal roles, NSD proteins represent promising therapeutic targets. The article further explores the advancements in targeted protein degradation (TPD) strategies, such as PROTACs and molecular glues, which offer a novel and highly effective approach to remove these proteins from cells. Recent successes in developing first-in-class degraders for NSD2 and NSD3 underscore the therapeutic potential of this modality. Continued research into the precise immunomodulatory mechanisms of NSDs and the development of selective protein degraders hold immense promise for enhancing cancer immunotherapy and overcoming resistance.

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