Prmt5, also known as Hsl7, Jbp1, Skb1, Capsuleen, or Dart5, is a predominant type II protein arginine methyltransferase. It catalyzes the mono-and symmetrical dimethylation of a wide range of histone and non-histone substrates, playing critical roles in numerous regulatory pathways, including those related to genome organization, transcription, cell cycle, and spliceosome assembly [3]. It is also involved in many normal cellular processes and is associated with cancer-related signaling pathways [1,2].

In high-risk neuroblastoma xenograft tumor models, pharmacologic or genetic inhibition of Prmt5 abolishes AKT1 arginine 15 methylation, preventing AKT1 translocation and subsequent activation, which in turn attenuates primary tumor growth and blocks metastasis [4]. In MTAP/CDKN2A-deleted cancers, depletion of Prmt5 impairs the viability of MTAP-deficient cancer cells as MTAP-deleted cells accumulate methylthioadenosine (MTA) that inhibits Prmt5 methyltransferase activity [5]. In triple-negative breast cancer, PRMT5 promotes ferroptosis resistance and impairs immunotherapy efficacy, and its inhibitors can potentiate immunotherapy [6]. In melanoma, reducing Prmt5 activity antagonizes melanoma growth in immunocompetent mice by affecting the cGAS/STING and NLRC5 pathways, and combination of Prmt5 inhibition with immune checkpoint therapy enhances therapeutic efficacy [7]. In colorectal cancer, Prmt5 methylating SMAD4 activates TGF-β signaling and promotes metastasis [8].

In conclusion, Prmt5 is essential for various cellular processes through its methylation functions. Studies using genetic inhibition or depletion models in different cancer types, such as neuroblastoma, MTAP/CDKN2A-deleted cancers, triple-negative breast cancer, melanoma, and colorectal cancer, have revealed its significance in tumor growth, metastasis, and response to immunotherapy. These findings suggest that Prmt5 could be a potential therapeutic target in these cancer conditions.