m1A inhibition fuels oncolytic virus-elicited antitumor immunity via downregulating PD-L1 expression
RNA N1-methyladenosine methylation (m1A) modification is critical in regulating mRNA translation and thus protein synthesis, but the role of m1A modification in the occurrence, progression, and immunotherapy of head and neck squamous cell cancer (HNSCC) remains largely unknown. In Tgfbr1/Pten 2cKO mice, we found that the spontaneous neoplastic transformation of oral mucosa is accompanied by elevated levels of m1A modification. Analysis of m1A-associated genes identified TRMT61A as the key m1A writer associated with cancer progression, and poor prognosis. Mechanically, TRMT61A-induced tRNA-m1A modification promotes MYC protein synthesis and subsequent programmed death-ligand 1 (PD-L1) expression. In Tgfbr1/Pten 2cKO mice, RNA-m1A modification levels are also elevated in tumors that developed resistance to oncolytic herpes simplex virus (oHSV) treatment. Therapeutic inhibition of m1A modification sustains oncolytic virus-induced antitumor immunity and reduces tumor growth, providing a promising strategy for alleviating resistance to oHSV therapy. These findings indicate that m1A inhibition can prevent immune escape after oHSV therapy by reducing the expression of PD-L1. Our results provide a mutually reinforcing strategy for clinical combination immunotherapy. Overall design: To explore whether TRMT61A plays a critical role in tumorigenesis, we screened and employed  lentivirus-mediated short hairpins RNAs (shRNAs) through their depletion efficiencies to silence TRMT61A expression in CAL-27/WSU-HN6 cell lines and treat shCtrl/shTRMT61A CAL-27 cells with either PBS or IFN?.