PRMT3 in cancer: arginine methylation as a driver of tumor metabolism, immune evasion, and therapeutic resistance

Protein arginine methyltransferase 3 (PRMT3) is a type I arginine methyltransferase that catalyzes asymmetric dimethylation of arginine residues on diverse substrate proteins. Initially characterized as a regulator of ribosomal protein methylation, PRMT3 has more recently been implicated in several cancer-related processes. Accumulating evidence suggests that PRMT3 is dysregulated in a variety of malignancies, including hepatocellular carcinoma, colorectal cancer, glioblastoma, breast cancer, pancreatic cancer, and non-small cell lung cancer. Through arginine methylation of selected regulatory proteins, PRMT3 has been linked to signaling pathways associated with tumor progression, metabolic adaptation, immune modulation, and therapeutic resistance. Mechanistically, available studies indicate that PRMT3 can regulate RNA-associated networks by methylating RNA-binding proteins and epitranscriptomic regulators such as IGF2BP1 and METTL14, thereby influencing mRNA stability and gene expression programs. In addition, PRMT3 has been reported to contribute to tumor metabolic reprogramming by promoting glycolytic activity and modulating amino acid metabolism through factors including HIF1A, PDHK1, and IDO1. These alterations may support tumor growth and, in some contexts, influence the tumor immune microenvironment. PRMT3 has also been associated with immune evasion, for example through effects on PD-L1 expression and innate immune signaling pathways such as cGAS–STING. Moreover, emerging evidence links PRMT3 to therapeutic resistance through mechanisms involving oncogenic transcript stabilization, immunometabolic remodeling, and drug efflux regulation. In this review, we summarize the current understanding of PRMT3 structure, catalytic mechanisms, and biological functions in cancer. We further discuss its emerging roles in metabolic regulation, immune suppression, and therapy resistance, while distinguishing mechanisms directly supported within specific cancer contexts from broader conceptual models inferred across studies. Overall, current evidence supports PRMT3 as an emerging and context-dependent regulator of tumor biology and a potential target for anticancer therapy.