Cancers commonly reprogram translation and metabolism, but little is known about how these two features coordinate in cancer stem cells. Here we show that glioblastoma stem cells (GSCs) display elevated protein translation. To dissect underlying mechanisms, we performed a CRISPR screen and identified YRDC as the top essential transfer RNA (tRNA) modification enzyme in GSCs. YRDC catalyzes the formation of N⁶-threonylcarbamoyladenosine (t⁶A) on ANN-decoding tRNA species (A denotes adenosine, and N denotes any nucleotide). Targeting YRDC reduced t⁶A formation, suppressed global translation and inhibited tumor growth both in vitro and in vivo. Threonine is an essential substrate of YRDC. Threonine accumulated in GSCs, which facilitated t⁶A formation through YRDC and shifted the proteome to support mitosis-related genes with ANN codon bias. Dietary threonine restriction (TR) reduced tumor t⁶A formation, slowed xenograft growth and augmented anti-tumor efficacy of chemotherapy and anti-mitotic therapy, providing a molecular basis for a dietary intervention in cancer treatment.

癌症通常会重新编程翻译和代谢，但人们对这两个特征在癌症干细胞中如何协调知之甚少。在这里，我们展示了胶质母细胞瘤干细胞（GSC）表现出升高的蛋白质翻译。为了剖析潜在机制，我们进行了 CRISPR 筛选，并确定 YRDC 是 GSC 中最重要的转移 RNA (tRNA) 修饰酶。 YRDC 催化 ANN 解码 tRNA 物种上N ⁶ -苏氨酰氨基甲酰基腺苷 (t ⁶ A)的形成（A 表示腺苷，N 表示任何核苷酸）。靶向 YRDC 可减少 t ⁶ A 形成，抑制全局翻译并抑制体外和体内肿瘤生长。苏氨酸是 YRDC 的重要底物。苏氨酸在 GSC 中积累，通过 YRDC 促进 t ⁶ A 形成，并改变蛋白质组以支持具有 ANN 密码子偏倚的有丝分裂相关基因。饮食苏氨酸限制（TR）减少了肿瘤t ⁶ A 的形成，减缓了异种移植物的生长，增强了化疗和抗有丝分裂治疗的抗肿瘤功效，为癌症治疗中的饮食干预提供了分子基础。