Protein arginine-methyltransferase 1 (PRMT1): a new pharmacological target in cholangiocarcinoma

Abstract

Cholangiocarcinoma (CCA) is a highly aggressive malignancy characterized by poor prognosis, limited therapeutic options, and a predominantly immunosuppressive tumor microenvironment. Protein arginine methyltransferase 1 (PRMT1), the major mediator of asymmetric arginine dimethylation, has been implicated in multiple oncogenic processes, although its role in CCA remains unknown. Here, we demonstrate that PRMT1 is frequently overexpressed in human CCA and is associated with aggressive molecular subtypes and immune-desert tumors. Genetic dependency analyses and pharmacological inhibition using type I PRMT inhibitors markedly impaired CCA cell proliferation, clonogenicity, and tumoroid growth. Transcriptomic profiling revealed that PRMT1 inhibition induces broad alterations in gene expression and alternative splicing, affecting pathways involved in proliferation, apoptosis, DNA damage response, metabolism, and immune signaling. Mechanistically, PRMT1 targeting promoted genomic stress, accumulation of cytosolic double-stranded DNA, and activation of the cGAS-STING-TBK1-IRF3 signaling axis, resulting in enhanced interferon signaling and increased expression of T cell-recruiting chemokines, including CXCL9 and CXCL10. PRMT1 inhibition also synergized with cisplatin, poly-ADP-ribose polymerase (PARP) inhibition, and PRMT5 blockade in vitro and in patient-derived tumoroids. Importantly, in an aggressive orthotopic murine model of intrahepatic CCA, combined treatment with the PRMT1 inhibitor GSK3368715 and anti-PD-1 antibodies significantly reduced tumor burden and increased CD4+ and CD8+ T-cell infiltration compared with monotherapies. Collectively, these findings identify PRMT1 as a critical regulator of CCA growth and immune evasion and support the therapeutic potential of PRMT1 inhibition, particularly in combination with immunotherapy.