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Human \u03b3\u03b4-T cells are indispensable for immunosurveillance toward malignant cells. However, their impact on \u03b3\u03b4-T cell metabolism and function remains poorly unexplored. Here, we applied targeted metabolomics analysis to serum FAs among cancer patients undergoing \u03b3\u03b4-T cell therapy and discovered that palmitic acid (PA) or oleic acid (OA) levels were associated with the efficacy of V\u03b39V\u03b42-T cell therapy. We further elucidated that PA suppresses the antitumor activity of V\u03b39V\u03b42-T cells by disrupting metabolic processes and inhibiting the secretion of lytic granules, whereas OA restores the impaired antitumor activity of V\u03b39V\u03b42-T cells. Mechanistically, we surprisingly found that PA stimulates V\u03b39V\u03b42-T cells to secrete excessive IFN\u03b3, which in turn induces cell pyroptosis, ultimately resulting in decreased antitumor activity. In contrast, OA reduces IFN\u03b3 secretion and mitigates cell pyroptosis, thereby restoring their antitumor activity. Alternatively, direct blockade of IFN\u03b3 by anti-IFN\u03b3 mAb or inhibition of pyroptosis by dimethyl fumarate (DMF) also restores their antitumor activity. This study highlights a novel mechanism whereby dietary FAs modulate \u03b3\u03b4-T cell function through regulating IFN\u03b3-mediated pyroptosis. Additionally, it offers proof-of-concept for an innovative approach by targeting IFN\u03b3-mediated pyroptosis or dietary OA supplementation to strengthen the antitumor immunity of \u03b3\u03b4-T cells against cancers.<\/jats:p>","DOI":"10.1038\/s41392-025-02295-8","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T23:02:04Z","timestamp":1751497324000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Oleic acid restores the impaired antitumor immunity of \u03b3\u03b4-T cells induced by palmitic acid"],"prefix":"10.1038","volume":"10","author":[{"given":"Yanmei","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lo Sha","family":"Cheung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiwei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manni","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6240-2409","authenticated-orcid":false,"given":"Howard Ho Wai","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenyao","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyue","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianze","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin Celeste","family":"Cheuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixin","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianfeng","family":"Zha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yashi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3834-0188","authenticated-orcid":false,"given":"Feifei","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5035-1111","authenticated-orcid":false,"given":"Yiwei","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4780-0289","authenticated-orcid":false,"given":"Yu-Lung","family":"Lau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinping","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6801-8798","authenticated-orcid":false,"given":"Wenwei","family":"Tu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,3]]},"reference":[{"key":"2295_CR1","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1161\/CIRCULATIONAHA.115.018585","volume":"133","author":"D Mozaffarian","year":"2016","unstructured":"Mozaffarian, D. 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