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Nonetheless, the specific molecular target and mechanism of action of SSRIs remain to be fully elucidated. Here, we reveal that citalopram exerts an immune-dependent anti-tumor effect in hepatocellular carcinoma (HCC). Interestingly, the anti-HCC effects of citalopram are not reliant on its conventional target, the serotonin transporter. Through various drug repurposing approaches, including global reverse gene expression profiling, drug affinity responsive target stability assay, and molecular docking, the complement component 5a receptor 1 (C5aR1) is identified as a new target of citalopram. C5aR1 is predominantly expressed by tumor-associated macrophages, and citalopram treatment enhances local macrophage phagocytosis and elicits CD8\n                    <jats:sup>+<\/jats:sup>\n                    T anti-tumor immunity. C5aR1 deficiency or depletion of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells hinders the anti-HCC effects of citalopram. Collectively, our study reveals the immunomodulatory roles of citalopram in inducing anti-tumor immunity and provides a basis for considering the repurposing of SSRIs as promising anticancer agents for HCC treatment.\n                  <\/jats:p>","DOI":"10.7554\/elife.103016","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T09:25:08Z","timestamp":1738142708000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.103016","source":"Crossref","is-referenced-by-count":1,"title":["Citalopram exhibits immune-dependent anti-tumor effects by modulating C5aR1+ TAMs"],"prefix":"10.7554","volume":"14","author":[{"given":"Fangyuan","family":"Dong","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013q1eq08","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Gastroenterology, Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai Institute of Geriatrics and Gerontology, Huadong Hospital, Fudan 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