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Regional delivery of CAR-T cells represents a new strategy to control tumor dissemination in serous cavities. However, malignant effusions constitute an immune-suppressive environment that potentially induces CAR-T cell dysfunction. Here, we demonstrated that the anti-tumor cytotoxicity of conventional 2nd-generation CAR-T cells was significantly inhibited by both the cellular and non-cellular components of MPE\/MA, which was primarily attributed to impaired CAR-T cell proliferation and cytokine production in MPE\/MA environment. Interestingly, we found that PD-L1 was widely expressed on freshly-isolated MPE\/MA cells. Based on this feature, a novel PD-L1-targeting chimeric switch receptor (PD-L1.BB CSR) was designed, which can bind to PD-L1, switching the inhibitory signal into an additional 4-1BB signal. When co-expressed with a 2nd-generation CAR, PD-L1.BB CSR-modified CAR-T cells displayed superior fitness and enhanced functions in both culture medium and MPE\/MA environment, causing rapid and durable eradication of pleural and peritoneal metastatic tumors in xenograft models. Further investigations revealed elevated expressions of T-cell activation, proliferation, and cytotoxicity-related genes, and we confirmed that PD-L1 scFv and 4-1BB intracellular domain, the two important components of PD-L1.BB CSR, were both necessary for the functional improvements of CAR-T cells. Overall, our study shed light on the clinical application of PD-L1.BB CSR-modified dual-targeting CAR-T cells. Based on this study, a phase I clinical trial was initiated in patients with pleural or peritoneal metastasis (NCT04684459).<\/jats:p>","DOI":"10.1038\/s41392-022-01198-2","type":"journal-article","created":{"date-parts":[[2022,11,19]],"date-time":"2022-11-19T03:08:55Z","timestamp":1668827335000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["A PD-L1-targeting chimeric switch receptor enhances efficacy of CAR-T cell for pleural and peritoneal metastasis"],"prefix":"10.1038","volume":"7","author":[{"given":"Qizhi","family":"Ma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benxia","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuchun","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejin","family":"Ou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiyu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei","family":"Shu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajuan","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diyuan","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8841-0781","authenticated-orcid":false,"given":"Jie","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Jing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeming","family":"Mo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kexun","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyang","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiting","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanting","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongsheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,11,19]]},"reference":[{"key":"1198_CR1","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1002\/jso.25453","volume":"120","author":"C Hodge","year":"2019","unstructured":"Hodge, C. & Badgwell, B. 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