Glutamine-driven metabolic reprogramming promotes CAR-T cell function through mTOR-SREBP2 mediated HMGCS1 upregulation in ovarian cancer
Abstract Background Chimeric antigen receptor T (CAR-T) cell therapy holds promise for cancer treatment, but its efficacy is often hindered by metabolic constraints in the tumor microenvironment. This study investigates the role of glutamine in enhancing CAR-T cell function against ovarian cancer. M...
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BMC
2025-07-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06853-0 |
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| author | Jiannan Chen Lianfeng Zhao Wenying Li Shuai Wang Jiayi Li Zhongyuan Lv Yaoyao Zhao Junqing Liang Zhigang Hu Feiyan Pan Lingfeng He Lili Gu Zhigang Guo |
| author_facet | Jiannan Chen Lianfeng Zhao Wenying Li Shuai Wang Jiayi Li Zhongyuan Lv Yaoyao Zhao Junqing Liang Zhigang Hu Feiyan Pan Lingfeng He Lili Gu Zhigang Guo |
| author_sort | Jiannan Chen |
| collection | DOAJ |
| description | Abstract Background Chimeric antigen receptor T (CAR-T) cell therapy holds promise for cancer treatment, but its efficacy is often hindered by metabolic constraints in the tumor microenvironment. This study investigates the role of glutamine in enhancing CAR-T cell function against ovarian cancer. Methods Metabolomic profiling of blood samples from ovarian cancer patients treated with MSLN-CAR-T cells was conducted to identify metabolic changes. In vitro, glutamine pretreatment was applied to CAR-T cells, and their proliferation, CAR expression, tumor lysis, and cytokine production (TNF-α, IFN-γ) were assessed. Mechanistic studies focused on the mTOR-SREBP2 pathway and its effect on HMGCS1 expression, membrane stability and immune synapse formation. In vivo, the antitumor effects and memory phenotype of glutamine-pretreated CAR-T cells were evaluated. Results Elevated glutamine levels were observed in the blood of ovarian cancer patients who responded to MSLN-CAR-T cell treatment. Glutamine pretreatment enhanced CAR-T cell proliferation, CAR expression, tumor lysis, and cytokine production. Mechanistically, glutamine activated the mTOR-SREBP2 pathway, upregulating HMGCS1 and promoting membrane stability and immune synapse formation. In vivo, glutamine-pretreated CAR-T cells exhibited superior tumor infiltration, sustained antitumor activity, and preserved memory subsets. Conclusions Our findings highlight glutamine-driven metabolic rewiring via the mTOR-SREBP2-HMGCS1 axis as a strategy to augment CAR-T cell efficacy in ovarian cancer. Trial registration NCT05372692 |
| format | Article |
| id | doaj-art-0f66f3dbe0c146cbb896cf2bb452e067 |
| institution | DOAJ |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-0f66f3dbe0c146cbb896cf2bb452e0672025-08-20T03:05:57ZengBMCJournal of Translational Medicine1479-58762025-07-0123111710.1186/s12967-025-06853-0Glutamine-driven metabolic reprogramming promotes CAR-T cell function through mTOR-SREBP2 mediated HMGCS1 upregulation in ovarian cancerJiannan Chen0Lianfeng Zhao1Wenying Li2Shuai Wang3Jiayi Li4Zhongyuan Lv5Yaoyao Zhao6Junqing Liang7Zhigang Hu8Feiyan Pan9Lingfeng He10Lili Gu11Zhigang Guo12Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal UniversityJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal UniversityJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal UniversityJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal UniversityJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal UniversityNanjing Calmhome Cell & Gene Engineering Institute Co., LtdJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal UniversityPeking University Cancer Hospital (Inner Mongolia Campus), Affiliated Cancer Hospital of Inner Mongolia Medical UniversityJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal UniversityJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal UniversityJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal UniversityNanjing Calmhome Cell & Gene Engineering Institute Co., LtdJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal UniversityAbstract Background Chimeric antigen receptor T (CAR-T) cell therapy holds promise for cancer treatment, but its efficacy is often hindered by metabolic constraints in the tumor microenvironment. This study investigates the role of glutamine in enhancing CAR-T cell function against ovarian cancer. Methods Metabolomic profiling of blood samples from ovarian cancer patients treated with MSLN-CAR-T cells was conducted to identify metabolic changes. In vitro, glutamine pretreatment was applied to CAR-T cells, and their proliferation, CAR expression, tumor lysis, and cytokine production (TNF-α, IFN-γ) were assessed. Mechanistic studies focused on the mTOR-SREBP2 pathway and its effect on HMGCS1 expression, membrane stability and immune synapse formation. In vivo, the antitumor effects and memory phenotype of glutamine-pretreated CAR-T cells were evaluated. Results Elevated glutamine levels were observed in the blood of ovarian cancer patients who responded to MSLN-CAR-T cell treatment. Glutamine pretreatment enhanced CAR-T cell proliferation, CAR expression, tumor lysis, and cytokine production. Mechanistically, glutamine activated the mTOR-SREBP2 pathway, upregulating HMGCS1 and promoting membrane stability and immune synapse formation. In vivo, glutamine-pretreated CAR-T cells exhibited superior tumor infiltration, sustained antitumor activity, and preserved memory subsets. Conclusions Our findings highlight glutamine-driven metabolic rewiring via the mTOR-SREBP2-HMGCS1 axis as a strategy to augment CAR-T cell efficacy in ovarian cancer. Trial registration NCT05372692https://doi.org/10.1186/s12967-025-06853-0CAR-T cell therapyT cell exhaustionGlutamineMTOR-SREBP2 AxisHMGCS1Ovarian cancer |
| spellingShingle | Jiannan Chen Lianfeng Zhao Wenying Li Shuai Wang Jiayi Li Zhongyuan Lv Yaoyao Zhao Junqing Liang Zhigang Hu Feiyan Pan Lingfeng He Lili Gu Zhigang Guo Glutamine-driven metabolic reprogramming promotes CAR-T cell function through mTOR-SREBP2 mediated HMGCS1 upregulation in ovarian cancer Journal of Translational Medicine CAR-T cell therapy T cell exhaustion Glutamine MTOR-SREBP2 Axis HMGCS1 Ovarian cancer |
| title | Glutamine-driven metabolic reprogramming promotes CAR-T cell function through mTOR-SREBP2 mediated HMGCS1 upregulation in ovarian cancer |
| title_full | Glutamine-driven metabolic reprogramming promotes CAR-T cell function through mTOR-SREBP2 mediated HMGCS1 upregulation in ovarian cancer |
| title_fullStr | Glutamine-driven metabolic reprogramming promotes CAR-T cell function through mTOR-SREBP2 mediated HMGCS1 upregulation in ovarian cancer |
| title_full_unstemmed | Glutamine-driven metabolic reprogramming promotes CAR-T cell function through mTOR-SREBP2 mediated HMGCS1 upregulation in ovarian cancer |
| title_short | Glutamine-driven metabolic reprogramming promotes CAR-T cell function through mTOR-SREBP2 mediated HMGCS1 upregulation in ovarian cancer |
| title_sort | glutamine driven metabolic reprogramming promotes car t cell function through mtor srebp2 mediated hmgcs1 upregulation in ovarian cancer |
| topic | CAR-T cell therapy T cell exhaustion Glutamine MTOR-SREBP2 Axis HMGCS1 Ovarian cancer |
| url | https://doi.org/10.1186/s12967-025-06853-0 |
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