{"doi":"10.1126/scisignal.adv4112","title":"CSF1R-CAR T cells induce CSF1R signaling and can promote target cell proliferation","abstract":"Chimeric antigen receptor (CAR) T cells have demonstrated unprecedented success in treating relapsed or refractory blood cancers. Previous studies of the mechanisms underlying the interactions and responses of CAR T cells and their targets have largely ignored the responses of tumors to CAR ligation. We compared the signaling of a second-generation, ligand-based CAR built from colony-stimulating factor 1 (CSF1) to target the CSF1 receptor (CSF1R) on target cells with a conventional, single-chain variable fragment-based CAR against the B cell antigen CD19. Using SILAC coculture with phosphotyrosine enrichment and LC-MS/MS analysis, we showed that ligation of CSF1R-expressing THP-1 cells with CSF1R-CAR T cells stimulated CSF1R-like signaling in the THP-1 cells. In contrast, no target cell signaling response was observed after the ligation of CD19-CAR T cells with target Raji cells. Using small-molecule inhibitors of the tyrosine kinase Lck, actin polymerization, and CSF1R, we found that CAR-induced CSF1R signaling in THP-1 cells depended exclusively on the kinase activity of CSF1R with no participation from T cell activation. Consistently, CSF1R-CAR T cells promoted THP-1 cell proliferation at low effector-to-target ratios but prevented THP-1 cell proliferation at high effector-to-target ratios. Our data provide evidence for CAR-induced signaling in target cells, an unintended consequence of CARs that may have implications for the choice of CAR antigen for optimal clinical efficacy.","journal":"Science Signaling","year":2025,"id":529297,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9542,"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":624028,"name":"Xinyan Zhang","orcid":"0000-0001-6269-3138","position":1,"is_corresponding":false},{"id":1408063,"name":"Amber Wang","orcid":"0000-0001-5073-3980","position":2,"is_corresponding":false},{"id":872358,"name":"Aisharja Mojumdar","orcid":"0000-0001-8407-0441","position":3,"is_corresponding":false},{"id":655749,"name":"Longhui Zeng","orcid":"0009-0008-2761-5570","position":4,"is_corresponding":false},{"id":301480,"name":"Xiaolei Su","orcid":"0000-0001-8696-7922","position":5,"is_corresponding":false},{"id":347401,"name":"Arthur R. Salomon","orcid":"0000-0002-7223-8996","position":6,"is_corresponding":false},{"id":822196,"name":"Kenneth P. Callahan","orcid":"0000-0003-4848-1512","position":0,"is_corresponding":true}],"reference_count":118,"raw_metadata":null,"created_at":"2026-07-19T02:50:56.971987Z","pmid":"41218104","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":[]}