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Here, TSHR is identified as specifically expressed in DTC, but absent in other normal tissues, making it an ideal target for CAR\u2010T therapy. To overcome CAR immunogenicity, a novel CAR molecule is engineered using TSH (TSH\u2010CAR), the natural ligand of TSHR, as the antigen\u2010binding domain to target TSHR. The TSH\u2010CAR\u2010T cells demonstrate effective antitumor activity against TSHR\u2010positive differentiated thyroid cancer (DTC) cell lines in vitro, accompanied by cytokine release (IFN\u03b3, IL\u20102) and robust proliferation. In addition, TSH\u2010CAR\u2010T cells achieved complete tumor eradication and sustained remission in two distinct thyroid cancer xenograft models. Furthermore, for comprehensively evaluate the safety profile of TSH\u2010CAR\u2010T cell, a murine TSH\u2010CAR (mTSH\u2010CAR\u2010T) is engineered, revealing that mTSH\u2010CAR\u2010T cells effectively control mTSHR\u2010positive tumor growth without evident on\u2010target\/off\u2010tumor effect in immunocompetent syngeneic mouse tumor models, except for the transient and reversible impairment of thyroid follicles, which is acceptable given prior thyroidectomy in DTC patients. The potent preclinical efficacy and favorable safety profile strongly support the clinical translation of TSH\u2010CAR\u2010T for patients suffering from metastatic and radioiodine\u2010resistant DTC.<\/jats:p>","DOI":"10.1002\/advs.202513243","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T11:02:24Z","timestamp":1758625344000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["TSH Ligand\u2010Based CAR\u2010T Cell Effectively Eradicates TSHR\u2010Positive Thyroid Cancer with Favorable Safety Profile"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1784-9409","authenticated-orcid":false,"given":"Fei","family":"Wang","sequence":"first","affiliation":[{"name":"Cancer Institute Xuzhou Medical University  209 Tongshan Road Xuzhou Jiangsu 221004 China"},{"name":"Center of Clinical Oncology the Affiliated Hospital of Xuzhou Medical University  99 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