SARDH in the 1-C metabolism sculpts the T-cell fate and serves as a potential cancer therapeutic target

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.