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<p>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 <i>SARDH</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月20日

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  • Wen Si,
  • Sijin Cheng,
  • Haiyin He,
  • Yu Zhang,
  • Yuhui Miao,
  • Dingcheng Yi,
  • Mengjiao Ni,
  • Anqiang Wang,
  • Hongtao Fan,
  • Yufei Bo,
  • Chang Liu,
  • Zhaode Bu,
  • Linnan Zhu,
  • Zemin Zhang

摘要

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.