SARDH in the 1-C metabolism sculpts the T-cell fate and serves as a potential cancer therapeutic target
Wen Si, Sijin Cheng, Haiyin He, Yu Zhang, Yuhui Miao, Dingcheng Yi, Michael Y. Ni, Anqiang Wang, Hongtao Fan, Yufei Bo, Chang Liu, Zhaode Bu, Linnan Zhu, Zemin Zhang
Abstract
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.