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

Wen Si^#^{1 2}, Sijin Cheng^#³, Haiyin He^#⁴, Yu Zhang⁵, Yuhui Miao³, Dingcheng Yi⁴, Mengjiao Ni⁶, Anqiang Wang⁷, Hongtao Fan⁴, Yufei Bo⁴, Chang Liu⁴, Zhaode Bu⁸, Linnan Zhu⁹, Zemin Zhang^{10 11 12}

Affiliations

¹ 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. siwen_bio@pku.edu.cn.
² Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China. siwen_bio@pku.edu.cn.
³ Institute for Data-Driven Tumor Immunology, Chongqing Medical University, Chongqing, China.
⁴ 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.
⁵ Changping Laboratory, Beijing, China.
⁶ Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
⁷ Gastrointestinal Cancer Center, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China.
⁸ State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China. buzhaode@cjcrcn.org.
⁹ 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. zhuln@pku.edu.cn.
¹⁰ 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. zemin@pku.edu.cn.
¹¹ Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China. zemin@pku.edu.cn.
¹² Institute for Data-Driven Tumor Immunology, Chongqing Medical University, Chongqing, China. zemin@pku.edu.cn.

^# Contributed equally.

PMID: 40830700
DOI: 10.1038/s41423-025-01331-5

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.

Keywords: 1-C metabolism; CD8+ exhausted T cells; Mitochondrial metabolism; SARDH; Sarcosine; Tumor microenvironment.

Cell Mol Immunol. 2025 Aug 20.doi: 10.1038/s41423-025-01331-5. (IF:21.8).

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

Abstract

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