Update on the Development of Targeting Arginine Methyltransferase PRMT5 in Cancer Research

Protein Arginine Methyltransferase 5 (PRMT5), the predominant type II PRMT, catalyzes symmetric dimethylation of both histone and non-histone substrates, thereby coordinating key cellular processes including gene expression, Ribonucleic Acid (RNA) splicing, cell cycle progression, and Deoxyribonucleic Acid (DNA) repair. Its frequent overexpression in various solid and hematologic malignancies contributes to tumorigenesis by promoting proliferation, metastasis, and immune evasion-mechanisms that involve silencing tumor suppressor genes, activating oncogenic signaling pathways such as PI3K-AKT, WNT-β-catenin, and NF-κB. These welldocumented oncogenic functions establish PRMT5 as a high-priority therapeutic target and highlight its synthetic lethal vulnerability in Methylthioadenosine Phosphorylase (MTAP)-deficient tumors, where accumulation of the endogenous PRMT5 inhibitor Methylthioadenosine (MTA) creates a unique therapeutic opportunity. Although PRMT5 is a well-validated oncogenic driver and more than a dozen inhibitors have entered clinical trials, none have yet gained regulatory approval. The lack of approved inhibitors underscores the urgent need for next-generation strategies, such as novel modulators with improved selectivity and reduced toxicity. Recent advances have led to the development of Proteolysis-Targeting Chimeras (PROTACs) that catalytically degrade PRMT5, which offers a mechanistically distinct avenue to overcome intrinsic and acquired resistance associated with conventional PRMT5 catalytic inhibitors. This review synthesizes current insights into PRMT5-driven tumorigenesis and tumor immunology, dissects structure-activity relationships, and charts the clinical progress of S-Adenosylmethionine (SAM)-competitive, substrate- competitive, MTA-cooperative, and PROTAC-based modalities. Finally, we outline precision medicine and combination strategies that could unlock the full therapeutic potential of PRMT5 targeting in oncology.