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Citalopram exhibits immune-dependent anti-tumor effects by modulating C5aR1 + TAMs
Open accessPreprint — published as 10.7554/elife.103016.4 · Paper page
Abstract
Administration of selective serotonin reuptake inhibitors (SSRIs) is associated with a reduced cancer risk and shows significant anti-tumor effects across multiple tumor types, suggesting the potential for repurposing SSRIs in cancer therapy. 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 effects 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 (TAMs), and citalopram treatment enhances local macrophage phagocytosis and elicits CD8 + T anti-tumor immunity. C5aR1 deficiency or depletion of CD8 + 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.
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Metadata
- Authors
- Dong, F., Zhang, S., Song, K., Jiang, L., Hu, L.-P., Li, Q., Zhang, X.-L., Li, J., Feng, M., Cai, Z.-W., Yao, H.-F., Li, R.-K., Li, H., Chen, J., Hu, X., Wang, J., Jiang, C., Zhu, H. H., Wang, C., Da, L.-T., Zhang, Z.-G., Bao, Z., Wang, X., & Jiang, S.-H.
- Affiliations
- Huadong Hospital (CN)
- Shanghai Cancer Institute (CN)
- Shanghai Jiao Tong University (CN)
- Renji Hospital (CN)
- Affiliated Hospital of Jiangsu University (CN)
- Corresponding author
- Jiang, Shu-Heng
- ORCID
- Venue
- eLife
- Publisher
- openRxiv
- Published
- 2024-10-18
- Volume
- 14
- ISSN
- 2050-084X (ISSN-L)
- OpenAlex
- W4403546925
- Cited by
- 1
- References
- 53
- Citations by year
- 2026: 1
- FWCI
- 2.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Funders
- National Natural Science Foundation of China (82472883)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- citalopram, selective serotonin reuptake inhibitors, drug repurposing, hepatocellular carcinoma, C5aR1, tumor-associated macrophages, macrophage phagocytosis, CD8+ T cells, antitumor immunity, immunomodulation
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