Yu Anze, Fu Liangmin, Jing Lanyu, Wang Yinghan, Ma Zifang, Zhou Xinwei, Yang Rui, Liu Jinhui, Hu Jiao, Feng Wei, Yang Taowei, Chen Zhenhua, Zu Xiongbing, Chen Wei, Chen Junxing, Luo Junhang
Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Cell Death Differ. 2025 Apr;32(4):776-791. doi: 10.1038/s41418-024-01434-y. Epub 2024 Dec 13.
The impact of amino acids on tumor immunotherapy is gradually being uncovered. In this study, we screened various essential and non-essential amino acids and found that methionine enhances mRNA methylation and reduced the activation of Type I interferon pathway in bladder cancer. Through RNA sequencing, point mutations, MB49 mouse tumor models, and single-cell RNA sequencing, we demonstrated that high methionine levels elevate the expression of mA reader YTHDF1, promoting the degradation of RIG-I, thereby inhibiting the RIG-I/MAVS-mediated IFN-I pathway and reducing the efficacy of tumor immunotherapy. Additionally, immunoprecipitation and mass spectrometry revealed that YTHDF1 binds to the eukaryotic translation initiation factor eIF5B, which acts on PD-L1 mRNA to enhance its translation and promote immune evasion. By intravesical administration of oncolytic bacteria VNP20009, we effectively depleted methionine locally, significantly prolonging mouse survival and enhancing immune cell infiltration and differentiation within tumors. Multiplex immunofluorescence assays in bladder cancer immunotherapy patients confirmed our findings. Our research elucidates two mechanisms by which methionine inhibits bladder cancer immunotherapy and proposes a targeted methionine depletion strategy that advances research while minimizing nutritional impact on patients.
氨基酸对肿瘤免疫治疗的影响正逐渐被揭示。在本研究中，我们筛选了各种必需氨基酸和非必需氨基酸，发现甲硫氨酸可增强mRNA甲基化并降低膀胱癌中I型干扰素途径的激活。通过RNA测序、点突变、MB49小鼠肿瘤模型和单细胞RNA测序，我们证明高甲硫氨酸水平会提高mA阅读器YTHDF1的表达，促进RIG-I的降解，从而抑制RIG-I/MAVS介导的IFN-I途径并降低肿瘤免疫治疗的疗效。此外，免疫沉淀和质谱分析表明，YTHDF1与真核翻译起始因子eIF5B结合，后者作用于PD-L1 mRNA以增强其翻译并促进免疫逃逸。通过膀胱内注射溶瘤细菌VNP20009，我们有效地在局部消耗了甲硫氨酸，显著延长了小鼠的生存期，并增强了肿瘤内免疫细胞的浸润和分化。对膀胱癌免疫治疗患者的多重免疫荧光分析证实了我们的发现。我们的研究阐明了甲硫氨酸抑制膀胱癌免疫治疗的两种机制，并提出了一种有针对性的甲硫氨酸消耗策略，该策略在推进研究的同时将对患者营养的影响降至最低。
