N¹-methyladenosine (m¹A) 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 m¹A modification levels. Analysis of m¹A-associated genes identified TRMT61A as a key m¹A writer linked to cancer progression and poor prognosis. Mechanistically, TRMT61A-mediated tRNA-m¹A modification promotes MYC protein synthesis, upregulating programmed death-ligand 1 (PD-L1) expression. Moreover, m¹A modification levels were also elevated in tumors treated with oncolytic herpes simplex virus (oHSV), contributing to reactive PD-L1 upregulation. Therapeutic m¹A inhibition sustained oHSV-induced antitumor immunity and reduced tumor growth, representing a promising strategy to alleviate resistance. These findings indicate that m¹A inhibition can prevent immune escape after oHSV therapy by reducing PD-L1 expression, providing a mutually reinforcing combination immunotherapy approach.

N¹-甲基腺苷 （m¹A） RNA 甲基化对调节 mRNA 翻译至关重要;然而，它在头颈部鳞状细胞癌 （HNSCC） 的发生、进展和免疫治疗反应中的作用在很大程度上仍然未知。使用 Tgfbr1 和 Pten 条件性敲除 （2cKO） 小鼠，我们发现口腔粘膜的肿瘤转化伴随着 m¹A 修饰水平的增加。对 m¹A 相关基因的分析确定TRMT61A是与癌症进展和不良预后相关的关键 m¹A 写入基因。从机制上讲，TRMT61A介导的 tRNA-m¹A 修饰促进 MYC 蛋白合成，上调程序性死亡配体 1 （PD-L1） 表达。此外，在用溶瘤性单纯疱疹病毒 （oHSV） 治疗的肿瘤中，m¹A 修饰水平也升高，导致反应性 PD-L1 上调。治疗性 m¹A 抑制维持了 oHSV 诱导的抗肿瘤免疫并减少肿瘤生长，代表了减轻耐药性的有前途的策略。这些发现表明，m¹A 抑制可以通过减少 PD-L1 表达来防止 oHSV 治疗后的免疫逃逸，提供了一种相辅相成的联合免疫治疗方法。