Oleic acid restores the impaired antitumor immunity of γδ-T cells induced by palmitic acid
Abstract Dietary fatty acids (FAs) are associated with the therapeutic intervention under various health conditions. Human γδ-T cells are indispensable for immunosurveillance toward malignant cells. However, their impact on γδ-T cell metabolism and function remains poorly unexplored. Here, we applie...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-07-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-025-02295-8 |
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| author | Yanmei Zhang Zheng Xiang Yan Xu Lo Sha Cheung Xiwei Wang Manni Wang Howard Ho Wai Wong Zhenyao Zhu Wenyue Zhang Yifan Gao Xianze Luo Yin Celeste Cheuk Yixin Zhou Xianfeng Zha Yashi Chen Man Li Feifei Luo Yiwei Chu Yu-Lung Lau Yinping Liu Wenwei Tu |
| author_facet | Yanmei Zhang Zheng Xiang Yan Xu Lo Sha Cheung Xiwei Wang Manni Wang Howard Ho Wai Wong Zhenyao Zhu Wenyue Zhang Yifan Gao Xianze Luo Yin Celeste Cheuk Yixin Zhou Xianfeng Zha Yashi Chen Man Li Feifei Luo Yiwei Chu Yu-Lung Lau Yinping Liu Wenwei Tu |
| author_sort | Yanmei Zhang |
| collection | DOAJ |
| description | Abstract Dietary fatty acids (FAs) are associated with the therapeutic intervention under various health conditions. Human γδ-T cells are indispensable for immunosurveillance toward malignant cells. However, their impact on γδ-T cell metabolism and function remains poorly unexplored. Here, we applied targeted metabolomics analysis to serum FAs among cancer patients undergoing γδ-T cell therapy and discovered that palmitic acid (PA) or oleic acid (OA) levels were associated with the efficacy of Vγ9Vδ2-T cell therapy. We further elucidated that PA suppresses the antitumor activity of Vγ9Vδ2-T cells by disrupting metabolic processes and inhibiting the secretion of lytic granules, whereas OA restores the impaired antitumor activity of Vγ9Vδ2-T cells. Mechanistically, we surprisingly found that PA stimulates Vγ9Vδ2-T cells to secrete excessive IFNγ, which in turn induces cell pyroptosis, ultimately resulting in decreased antitumor activity. In contrast, OA reduces IFNγ secretion and mitigates cell pyroptosis, thereby restoring their antitumor activity. Alternatively, direct blockade of IFNγ by anti-IFNγ mAb or inhibition of pyroptosis by dimethyl fumarate (DMF) also restores their antitumor activity. This study highlights a novel mechanism whereby dietary FAs modulate γδ-T cell function through regulating IFNγ-mediated pyroptosis. Additionally, it offers proof-of-concept for an innovative approach by targeting IFNγ-mediated pyroptosis or dietary OA supplementation to strengthen the antitumor immunity of γδ-T cells against cancers. |
| format | Article |
| id | doaj-art-e806d1e90bd3499d848ff8dba69f4630 |
| institution | Kabale University |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-e806d1e90bd3499d848ff8dba69f46302025-08-20T03:45:41ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-07-0110111710.1038/s41392-025-02295-8Oleic acid restores the impaired antitumor immunity of γδ-T cells induced by palmitic acidYanmei Zhang0Zheng Xiang1Yan Xu2Lo Sha Cheung3Xiwei Wang4Manni Wang5Howard Ho Wai Wong6Zhenyao Zhu7Wenyue Zhang8Yifan Gao9Xianze Luo10Yin Celeste Cheuk11Yixin Zhou12Xianfeng Zha13Yashi Chen14Man Li15Feifei Luo16Yiwei Chu17Yu-Lung Lau18Yinping Liu19Wenwei Tu20Department of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Microbiology and Immunology, Health Science Center, School of Medicine, Jinan UniversityGuangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People’s Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan UniversityDepartment of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Clinical Laboratory, The First Affiliated Hospital, Jinan UniversityGuangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People’s Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan UniversityGuangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People’s Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan UniversityDepartment of Digestive Diseases, Huashan Hospital, Fudan UniversityDepartment of Immunology, School of Basic Medical Sciences, Biotherapy Research Center and Institutes of Biomedical Sciences, Fudan UniversityDepartment of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong KongAbstract Dietary fatty acids (FAs) are associated with the therapeutic intervention under various health conditions. Human γδ-T cells are indispensable for immunosurveillance toward malignant cells. However, their impact on γδ-T cell metabolism and function remains poorly unexplored. Here, we applied targeted metabolomics analysis to serum FAs among cancer patients undergoing γδ-T cell therapy and discovered that palmitic acid (PA) or oleic acid (OA) levels were associated with the efficacy of Vγ9Vδ2-T cell therapy. We further elucidated that PA suppresses the antitumor activity of Vγ9Vδ2-T cells by disrupting metabolic processes and inhibiting the secretion of lytic granules, whereas OA restores the impaired antitumor activity of Vγ9Vδ2-T cells. Mechanistically, we surprisingly found that PA stimulates Vγ9Vδ2-T cells to secrete excessive IFNγ, which in turn induces cell pyroptosis, ultimately resulting in decreased antitumor activity. In contrast, OA reduces IFNγ secretion and mitigates cell pyroptosis, thereby restoring their antitumor activity. Alternatively, direct blockade of IFNγ by anti-IFNγ mAb or inhibition of pyroptosis by dimethyl fumarate (DMF) also restores their antitumor activity. This study highlights a novel mechanism whereby dietary FAs modulate γδ-T cell function through regulating IFNγ-mediated pyroptosis. Additionally, it offers proof-of-concept for an innovative approach by targeting IFNγ-mediated pyroptosis or dietary OA supplementation to strengthen the antitumor immunity of γδ-T cells against cancers.https://doi.org/10.1038/s41392-025-02295-8 |
| spellingShingle | Yanmei Zhang Zheng Xiang Yan Xu Lo Sha Cheung Xiwei Wang Manni Wang Howard Ho Wai Wong Zhenyao Zhu Wenyue Zhang Yifan Gao Xianze Luo Yin Celeste Cheuk Yixin Zhou Xianfeng Zha Yashi Chen Man Li Feifei Luo Yiwei Chu Yu-Lung Lau Yinping Liu Wenwei Tu Oleic acid restores the impaired antitumor immunity of γδ-T cells induced by palmitic acid Signal Transduction and Targeted Therapy |
| title | Oleic acid restores the impaired antitumor immunity of γδ-T cells induced by palmitic acid |
| title_full | Oleic acid restores the impaired antitumor immunity of γδ-T cells induced by palmitic acid |
| title_fullStr | Oleic acid restores the impaired antitumor immunity of γδ-T cells induced by palmitic acid |
| title_full_unstemmed | Oleic acid restores the impaired antitumor immunity of γδ-T cells induced by palmitic acid |
| title_short | Oleic acid restores the impaired antitumor immunity of γδ-T cells induced by palmitic acid |
| title_sort | oleic acid restores the impaired antitumor immunity of γδ t cells induced by palmitic acid |
| url | https://doi.org/10.1038/s41392-025-02295-8 |
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