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Current CAR-T cell therapies for osteosarcoma are predominantly designed with single targets, but their efficacy remains unsatisfactory. In this study, a novel bispecific CAR-T cell was developed to provide an experimental basis for improving the therapeutic outcome of osteosarcoma. Single-cell RNA sequencing (scRNA-seq) identified two antigens highly expressed in osteosarcoma cells, ANXA2 and CD147, whose expression was further validated at the tissue level by qRT-PCR, flow cytometry, and immunohistochemistry. Based on a second-generation CAR backbone, a bispecific ANXA2\/CD147 CAR-T construct was generated using magnetic bead sorting, primary T-cell culture, and lentiviral transduction, achieving a transduction efficiency of 47.1%. LDH release assays demonstrated that bispecific CAR-T cells exhibited significantly greater cytotoxicity against tumor cells than single-target and control groups. ELISA confirmed that bispecific CAR-T cells released higher levels of effector molecules, including GZMB and TNF\u03b1. In a subcutaneous CDX model, bispecific CAR-T cells displayed superior antitumor activity and greater T-cell infiltration. In a paw pad xenograft model, mice treated with bispecific CAR-T cells exhibited the smallest tumor volumes, lowest tumor weights, and reduced rates of lymph node metastasis. Furthermore, PDX models confirmed that bispecific CAR-T cells effectively suppressed osteosarcoma growth. ScRNA-seq of tumors derived from CDX models and immunohistochemistry revealed markedly increased infiltration of M1 macrophages in the bispecific group. Collectively, this study successfully generated a bispecific ANXA2\/CD147 CAR-T cell with robust antitumor activity, providing a promising new strategy for the immunotherapy of osteosarcoma.<\/jats:p>","DOI":"10.1038\/s41388-026-03926-2","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T18:07:46Z","timestamp":1785780466000},"page":"4037-4050","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Bispecific ANXA2\/CD147 CAR-T cell therapy for osteosarcoma"],"prefix":"10.1038","volume":"45","author":[{"given":"Hai-Jun","family":"Tang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan-Ting","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He-Ning","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Xiu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Ming","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuan","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Mai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan-Hang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shang-Yu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Yu","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Hua","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3563-763X","authenticated-orcid":false,"given":"Mao-Lin","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Li","family":"Zhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7745-1083","authenticated-orcid":false,"given":"Yun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"3926_CR1","doi-asserted-by":"publisher","first-page":"vii320","DOI":"10.1093\/annonc\/mdq276","volume":"21","author":"J Ritter","year":"2010","unstructured":"Ritter J, Bielack SS. 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All procedures used for data generation in this study were conducted in accordance with applicable guidelines and regulations. The human research conformed to the Declaration of Helsinki, and written informed consent was obtained from all participants. The animal experiments were conducted in accordance with applicable institutional animal care and use guidelines and are reported in accordance with the ARRIVE guidelines.","order":2,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Ethics"}}]}}