PCIF1-mediated depletion of N6,2’-O-dimethyladenosine in MSH2-cGAS-STING axis promote tumor radiosensitivity

Phosphorylated CTD-interacting factor 1(PCIF1) was the first reported RNA N6,2’-O- dimethyladenosine(m6Am) methyltransferase. However, the association between PCIF1 and m6Am modifications in response to radiotherapy remains ambiguous. RNA sequencing revealed that PCIF1 was downregulated after radiotherapy. The biological effects of PCIF1 were investigated using both in vitro and in vivo models. Genome-wide N6,2′-O-dimethyladenosine (m6Am)-exo-seq and MeRIP-PCR were performed to identify MSH2 as a downstream target of PCIF1. Here, we report that the expression of PCIF1 is elevated in tumors but decreased after irradiation. The deletion of PCIF1 in KPC and B16 cells prevented cell growth in vitro and slowed the growth of tumors in mice. PCIF1 deletion also mediated radiosensitization by promoting apoptosis. Furthermore, PCIF1 deletion inhibited MSH2 translation via m6Am modification, contributing to DNA damage and activation of the cGAS-STING pathway. Moreover, PCIF1 deletion enhancd the antitumor efficacy of radiotherapy combined with anti-PD-1 therapy. Examination of the underlying mechanism revealed that PCIF1 deletion enhances the infiltration of CD4 + and CD8 + T cells. In summary, we revealed the oncogenic and radioresistance-promoting roles of PCIF1, with novel implications for m6Am modification in radiotherapy and immunotherapy (Abstract figure).