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  3. Oleic acid restores the impaired antitumor immunity of γδ-T cells induced by palmitic acid

Oleic acid restores the impaired antitumor immunity of γδ-T cells induced by palmitic acid

  • Signal Transduct Target Ther. 2025 Jul 3;10(1):209. doi: 10.1038/s41392-025-02295-8.
Yanmei Zhang 1,  Zheng Xiang 2 3,  Yan Xu 4 5,  Lo Sha Cheung 1,  Xiwei Wang 1,  Manni Wang 1,  Howard Ho Wai Wong 1,  Zhenyao Zhu 1,  Wenyue Zhang 1,  Yifan Gao 1,  Xianze Luo 1,  Yin Celeste Cheuk 1,  Yixin Zhou 1,  Xianfeng Zha 6,  Yashi Chen 4,  Man Li 4,  Feifei Luo 7,  Yiwei Chu 8,  Yu-Lung Lau 1,  Yinping Liu 1,  Wenwei Tu 9 10
Affiliations

Affiliations

  • 1 Department of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 2 Department of Microbiology and Immunology, Health Science Center, School of Medicine, Jinan University, Guangzhou, Guangdong, China.
  • 3 Key Laboratory of Viral Pathogenesis & Infection Prevention and Control, Jinan University, Ministry of Education, Guangzhou, Guangdong, China.
  • 4 Guangdong 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 University, Zhuhai, Guangdong, China.
  • 5 State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center, School of Medicine, Jinan University, Guangzhou, Guangdong, China.
  • 6 Department of Clinical Laboratory, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China.
  • 7 Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China.
  • 8 Department of Immunology, School of Basic Medical Sciences, Biotherapy Research Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
  • 9 Department of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. wwtu@hku.hk.
  • 10 CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. wwtu@hku.hk.
PMID: 40603316 DOI: 10.1038/s41392-025-02295-8
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.

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