Si Wen, Cheng Sijin, He Haiyin, Zhang Yu, Miao Yuhui, Yi Dingcheng, Ni Mengjiao, Wang Anqiang, Fan Hongtao, Bo Yufei, Liu Chang, Bu Zhaode, Zhu Linnan, Zhang Zemin
Biomedical Pioneering Innovation Center (BIOPIC) and School of Life Sciences, State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, Peking University, Beijing, China.
Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
Cell Mol Immunol. 2025 Aug 20. doi: 10.1038/s41423-025-01331-5.
T-cell metabolism plays a pivotal role in defining T-cell functional states. Through analysis of a comprehensive pancancer single-cell transcriptional atlas, we identified SARDH, an enzyme involved in one-carbon (1-C) metabolism, as a potential T-cell metabolic checkpoint. SARDH significantly impacts T-cell fate and function, leading to impaired tumor control efficacy. Knocking down SARDH resulted in sarcosine accumulation and reduced consumption of S-adenosylmethionine (SAM), a critical methyl donor for epigenetic modulation, likely due to the shift in glycine-to-sarcosine homeostasis. Deletion of SARDH increased H3K79me2 modification at NF-κB-activating genes, thereby augmenting NF-κB signaling and T-cell function. Additionally, we observed transcriptional dysregulation of 1-C metabolism within tumors across various cancer types, which was often accompanied by increased sarcosine levels. Sarcosine was found to induce SARDH upregulation, suggesting a feedback mechanism for metabolic homeostasis in T cells within tumors. These findings underscore the potential effects and mechanism of targeting 1-C metabolism, particularly SARDH, as an avenue for cancer therapy.
T细胞代谢在决定T细胞功能状态中起着关键作用。通过对一份全面的泛癌单细胞转录图谱进行分析，我们确定了参与一碳（1-C）代谢的一种酶——琥珀酸半醛脱氢酶（SARDH），它是一个潜在的T细胞代谢检查点。SARDH对T细胞命运和功能有显著影响，导致肿瘤控制疗效受损。敲低SARDH会导致肌氨酸积累，并减少S-腺苷甲硫氨酸（SAM，一种用于表观遗传调控的关键甲基供体）的消耗，这可能是由于甘氨酸-肌氨酸内稳态的改变所致。删除SARDH会增加NF-κB激活基因处的H3K79me2修饰，从而增强NF-κB信号传导和T细胞功能。此外，我们观察到在各种癌症类型的肿瘤中，1-C代谢存在转录失调，这通常伴随着肌氨酸水平的升高。发现肌氨酸可诱导SARDH上调，这表明肿瘤内T细胞代谢稳态存在一种反馈机制。这些发现强调了靶向1-C代谢，特别是SARDH作为一种癌症治疗途径的潜在作用和机制。
