Cancer cells selectively promote translation of specific oncogenic transcripts to facilitate cancer survival and progression, but the underlying mechanisms are poorly understood. Here, we find that N⁷-methylguanosine (m⁷G) tRNA modification and its methyltransferase complex components, METTL1 and WDR4, are significantly upregulated in intrahepatic cholangiocarcinoma (ICC) and associated with poor prognosis. We further reveal the critical role of METTL1/WDR4 in promoting ICC cell survival and progression using loss- and gain-of-function assays in vitro and in vivo. Mechanistically, m⁷G tRNA modification selectively regulates the translation of oncogenic transcripts, including cell-cycle and epidermal growth factor receptor (EGFR) pathway genes, in m⁷G-tRNA-decoded codon-frequency-dependent mechanisms. Moreover, using overexpression and knockout mouse models, we demonstrate the crucial oncogenic function of Mettl1-mediated m⁷G tRNA modification in promoting ICC tumorigenesis and progression in vivo. Our study uncovers the important physiological function and mechanism of METTL1-mediated m⁷G tRNA modification in the regulation of oncogenic mRNA translation and cancer progression.

癌细胞选择性地促进特定致癌转录物的翻译以促进癌症存活和进展，但其潜在机制知之甚少。在这里，我们发现 N ^{7 -}甲基鸟苷(m ⁷ G) tRNA 修饰及其甲基转移酶复合物成分 METTL1 和 WDR4 在肝内胆管癌 (ICC) 中显着上调，并与不良预后相关。我们进一步揭示了 METTL1/WDR4 在促进 ICC 细胞存活和进展中的关键作用，使用体外和体内的功能丧失和获得试验。机械上，m ⁷G tRNA 修饰在 m ⁷ G-tRNA 解码的密码子频率依赖性机制中选择性地调节致癌转录物的翻译，包括细胞周期和表皮生长因子受体 (EGFR) 通路基因。此外，使用过表达和敲除小鼠模型，我们证明了 Mettl1 介导的 m ⁷ G tRNA 修饰在促进体内ICC 肿瘤发生和进展中的关键致癌功能。我们的研究揭示了 METTL1 介导的 m ⁷ G tRNA 修饰在调控致癌 mRNA 翻译和癌症进展中的重要生理功能和机制。