{"doi":"10.1016/j.cell.2025.04.032","title":"Serotonin transporter inhibits antitumor immunity through regulating the intratumoral serotonin axis","abstract":"Identifying additional immune checkpoints hindering antitumor T cell responses is key to the development of next-generation cancer immunotherapies. Here, we report the induction of serotonin transporter (SERT), a regulator of serotonin levels and physiological functions in the brain and peripheral tissues, in tumor-infiltrating CD8 T cells. Inhibition of SERT using selective serotonin reuptake inhibitors (SSRIs), the most widely prescribed antidepressants, significantly suppressed tumor growth and enhanced T cell antitumor immunity in various mouse syngeneic and human xenograft tumor models. Importantly, SSRI treatment exhibited significant therapeutic synergy with programmed cell death protein 1 (PD-1) blockade, and clinical data correlation studies negatively associated intratumoral SERT expression with patient survival in a range of cancers. Mechanistically, SERT functions as a negative-feedback regulator inhibiting CD8 T cell reactivities by depleting intratumoral T cell-autocrine serotonin. These findings highlight the significance of the intratumoral serotonin axis and identify SERT as an immune checkpoint, positioning SSRIs as promising candidates for cancer immunotherapy.","journal":"Cell","year":2025,"id":508943,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":60,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9643,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1362606,"name":"James Elsten-Brown","orcid":null,"position":1,"is_corresponding":false},{"id":507121,"name":"Miao Li","orcid":"0000-0003-0891-1143","position":2,"is_corresponding":false},{"id":976827,"name":"Enbo Zhu","orcid":"0000-0001-8600-8553","position":3,"is_corresponding":false},{"id":533101,"name":"Zhe Li","orcid":"0000-0002-9357-6839","position":4,"is_corresponding":false},{"id":1361440,"name":"Yuning Chen","orcid":"0009-0000-8010-670X","position":5,"is_corresponding":false},{"id":1361441,"name":"Elliot Kang","orcid":"0000-0002-0001-1186","position":6,"is_corresponding":false},{"id":236682,"name":"Feiyang Ma","orcid":"0000-0002-6260-0787","position":7,"is_corresponding":false},{"id":1361442,"name":"Jennifer Chiang","orcid":"0000-0003-3026-2055","position":8,"is_corresponding":false},{"id":627558,"name":"Yan-Ruide Li","orcid":"0000-0002-9858-300X","position":9,"is_corresponding":false},{"id":1191887,"name":"Yichen Zhu","orcid":"0000-0002-8772-2860","position":10,"is_corresponding":false},{"id":646649,"name":"Jie Huang","orcid":"0000-0002-4247-463X","position":11,"is_corresponding":false},{"id":231694,"name":"Audrey Fung","orcid":"0000-0001-5375-2853","position":12,"is_corresponding":false},{"id":1362607,"name":"Quentin Scarborough","orcid":null,"position":13,"is_corresponding":false},{"id":1362608,"name":"Robin Cadd","orcid":null,"position":14,"is_corresponding":false},{"id":329777,"name":"Jin Zhou","orcid":"0000-0001-7983-0274","position":15,"is_corresponding":false},{"id":822206,"name":"Arnold I. Chin","orcid":"0000-0002-6714-9200","position":16,"is_corresponding":false},{"id":40483,"name":"Matteo Pellegrini","orcid":"0000-0001-9355-9564","position":17,"is_corresponding":false},{"id":627561,"name":"Lili Yang","orcid":"0000-0001-6568-0404","position":18,"is_corresponding":false},{"id":646646,"name":"Bo Li","orcid":"0000-0002-5661-7961","position":0,"is_corresponding":true}],"reference_count":144,"raw_metadata":null,"created_at":"2026-07-19T02:47:00.188082Z","pmid":"40403728","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}