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m1A inhibition fuels oncolytic virus-elicited antitumor immunity via downregulating MYC/PD-L1 signaling

Li Shujin,Feng Tian,Liu Yuantong,Yang Qichao,Song An,Wang Shuo,Xie Jun,Zhang Junjie,Yuan Bifeng,Sun Zhijun

N 1 -methyladenosine (m 1 A) RNA methylation is critical for regulating mRNA translation; however, its role in the development, progression, and immunotherapy response of head and neck squamous cell carcinoma (HNSCC) remains largely unknown. Using Tgfbr1 and Pten conditional knockout (2cKO) mice, we found the neoplastic transformation of oral mucosa was accompanied by increased m 1 A modification levels. Analysis of m 1 A-associated genes identified TRMT61A as a key m 1 A writer linked to cancer progression and poor prognosis. Mechanistically, TRMT61A-mediated tRNA-m 1 A modification promotes MYC protein synthesis, upregulating programmed death-ligand 1 (PD-L1) expression. Moreover, m 1 A modification levels were also elevated in tumors treated with oncolytic herpes simplex virus (oHSV), contributing to reactive PD-L1 upregulation. Therapeutic m 1 A inhibition sustained oHSV-induced antitumor immunity and reduced tumor growth, representing a promising strategy to alleviate resistance. These findings indicate that m 1 A inhibition can prevent immune escape after oHSV therapy by reducing PD-L1 expression, providing a mutually reinforcing combination immunotherapy approach.