{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:04:15Z","timestamp":1790701455037,"version":"4.1.0"},"reference-count":26,"publisher":"IMR Press","issue":"9","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Construction Fund of Wenzhou Municipal Science and Technology Research Program","award":["ZS2017014"],"award-info":[{"award-number":["ZS2017014"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: Breast cancer continues to be a major global health burden, with a significant proportion of patients developing metastatic or treatment-resistant disease. Novel therapeutic strategies are urgently needed. Nectin cell adhesion molecule 4 (Nectin4), an adhesion molecule overexpressed in aggressive breast cancer subtypes, represents a promising target for immunotherapy due to its restricted expression in normal tissues. This study investigated the therapeutic potential of Nectin4-directed chimeric antigen receptor natural killer (CAR-NK) cell therapy against triple-negative breast cancer (TNBC) at the preclinical stage. Methods: Human natural killer (NK) cells obtained from peripheral blood from healthy donors were engineered to express an anti-Nectin4 chimeric antigen receptor (CAR) via lentiviral transduction, expanded ex vivo, and then used for functional studies. Cytotoxic activity was assessed in vitro against Nectin4-high-expressing breast cancer cells using luciferase-based killing assays at various effector-to-target ratios. In vivo efficacy was evaluated in NOD\/SCID\/IL2r\u03b3null (NSG) mice bearing subcutaneous breast cancer tumors treated with CAR-NK cells, compared to untransduced NK cells and phosphate-buffered saline controls. Tumor growth was monitored using bioluminescence imaging and harvested tumors were subsequently analyzed for Nectin4 expression using immunohistochemistry. Results: CAR-NK cells potently and specifically lysed Nectin4-positive breast cancer cells in vitro, with up to 95% target cell lysis at an effector-to-target ratio of 5:1. In vivo, CAR-NK treatment reduced tumor burden and prolonged survival compared with controls. Immunohistochemical analysis revealed a marked reduction in Nectin4 expression within tumors from the CAR-NK-treated group, consistent with targeted tumor cell elimination. Conclusions: CAR-NK cells targeting Nectin4 demonstrated potent cytotoxic activity in vitro and effectively suppressed tumor growth in vivo, supporting the further evaluation of Nectin4 as a therapeutic target for CAR-NK-based immunotherapy in TNBC, particularly for aggressive subtypes with limited treatment options.<\/jats:p>","DOI":"10.31083\/fbl54654","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:21:51Z","timestamp":1790698911000},"source":"Crossref","is-referenced-by-count":0,"title":["Nectin4 as a Promising Target for CAR-NK Cell Therapy in Breast Cancer Treatment"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0221-1752","authenticated-orcid":true,"given":"Jianchun","family":"Lian","sequence":"first","affiliation":[{"name":"Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, 325035 Wenzhou, Zhejiang, China"},{"name":"Department of Medical Laboratory, The Affiliated Huaian No.1 People\u2019s Hospital of Nanjing Medical University, 223300 Huaian, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6220-2052","authenticated-orcid":true,"given":"Xinyu","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, 325035 Wenzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2337-2501","authenticated-orcid":true,"given":"Tianlong","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, 325035 Wenzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1734-305X","authenticated-orcid":true,"given":"Tingwei","family":"Zhu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, 325035 Wenzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3585-2797","authenticated-orcid":true,"given":"Xin","family":"Huang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, 325035 Wenzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0728-6905","authenticated-orcid":true,"given":"Cheng","family":"Wei","sequence":"additional","affiliation":[{"name":"Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, 325035 Wenzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5110-1429","authenticated-orcid":true,"given":"Ai","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Geriatric, Affiliated Hangzhou First People\u2019s Hospital, Westlake University School of Medicine, 310022 Hangzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3911-043X","authenticated-orcid":true,"given":"Jimin","family":"Gao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, 325035 Wenzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. 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