{"doi":"10.1101/2025.06.09.658618","title":"DR5 CAR-T cells target solid tumors and suppress MDSCs with minimal toxicity","abstract":"Abstract Chimeric antigen receptor (CAR) T cell therapies have poor efficacy in solid tumors due to limited target specificity and an immunosuppressive tumor microenvironment. We investigated death receptor 5 (DR5) as a CAR target based on its high expression in both solid tumors and myeloid- derived suppressor cells (MDSCs). We engineered agonistic DR5-specific CAR constructs and evaluated their activity in multiple models, demonstrating DR5-expression-dependent tumor killing, confirmed by knockout and overexpression experiments. DR5-targeting single-chain variable fragments retained their pro-apoptotic activity when expressed on non-effector cells or extracellular vesicles. Among multiple CAR designs, we identified a construct with optimized binding affinity that maintained T cell viability while preserving strong tumor and MDSC-killing potency. To assess safety and efficacy in an immunocompetent setting, we also developed a murine DR5-targeted CAR. In multiple xenograft and syngeneic mouse models, DR5 CAR-T cells reduced tumor growth, prolonged survival, and did not cause detectable toxicity. In patient- derived organoids and tissue slices, DR5 CAR-T cells infiltrated tumor tissues, reduced MDSCs, boosted CD8+ T cell activity, and inhibited tumor growth. These findings support DR5-targeted CAR-T therapy as a promising strategy for treating solid tumors, which combines direct tumor cytotoxicity with immune activation and minimizes off-target effects. Teaser DR5 CAR-T cells eliminate tumor cells and MDSCs and activate tumor-resident CD8+ T cells within the TME.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":567990,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9579,"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":662037,"name":"Shujing Liu","orcid":"0000-0002-2958-093X","position":1,"is_corresponding":false},{"id":697063,"name":"Prithvi Sinha","orcid":"0000-0002-0667-7974","position":2,"is_corresponding":false},{"id":1329748,"name":"Fang Liu","orcid":"0000-0002-1780-1723","position":3,"is_corresponding":false},{"id":1443540,"name":"Xiaogang Zhang","orcid":"0000-0002-2280-403X","position":4,"is_corresponding":false},{"id":731209,"name":"Yeye Guo","orcid":"0000-0002-8352-1121","position":5,"is_corresponding":false},{"id":1332735,"name":"Beatriz Gonçalves","orcid":"0000-0002-5220-7383","position":6,"is_corresponding":false},{"id":1444056,"name":"Qiuxiang Zheng","orcid":null,"position":7,"is_corresponding":false},{"id":64925,"name":"Haiwei Mou","orcid":"0000-0002-1710-1882","position":8,"is_corresponding":false},{"id":845625,"name":"Jingbo Yang","orcid":"0000-0002-6653-2873","position":9,"is_corresponding":false},{"id":852794,"name":"Lili Huang","orcid":"0000-0002-4486-3532","position":10,"is_corresponding":false},{"id":227865,"name":"John Scholler","orcid":"0000-0002-9725-6277","position":11,"is_corresponding":false},{"id":932633,"name":"Fei Miao","orcid":"0000-0003-4683-1558","position":12,"is_corresponding":false},{"id":1443541,"name":"Tingting Zeng","orcid":"0000-0002-6038-2843","position":13,"is_corresponding":false},{"id":251288,"name":"Giorgos C. Karakousis","orcid":"0000-0002-9321-2795","position":14,"is_corresponding":false},{"id":105478,"name":"Alexander C. Huang","orcid":"0000-0002-0099-0492","position":15,"is_corresponding":false},{"id":251287,"name":"Tara C. Mitchell","orcid":"0000-0002-8186-7284","position":16,"is_corresponding":false},{"id":3837,"name":"Ravi K. Amaravadi","orcid":"0000-0002-5768-2474","position":17,"is_corresponding":false},{"id":253112,"name":"Lynn M. Schuchter","orcid":null,"position":18,"is_corresponding":false},{"id":242813,"name":"Michael C. Milone","orcid":"0000-0002-1580-9844","position":19,"is_corresponding":false},{"id":654857,"name":"Wei Guo","orcid":"0000-0002-9251-0360","position":20,"is_corresponding":false},{"id":227870,"name":"Carl H. 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