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)meta...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.展开更多
基金supported by funding from the National Key Research and Development Program of China(2023YFF1204700)the National Natural Science Foundation of China(L2424217,92459001,and 92259205).
文摘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.
