TSH Ligand‐Based CAR‐T Cell Effectively Eradicates TSHR‐Positive Thyroid Cancer with Favorable Safety Profile

Abstract CAR‐T therapy faces significant challenges in solid tumors, including the shortage of targetable antigen and the immunogenicity of CAR molecules. Here, TSHR is identified as specifically expressed in DTC, but absent in other normal tissues, making it an ideal target for CAR‐T therapy. To overcome CAR immunogenicity, a novel CAR molecule is engineered using TSH (TSH‐CAR), the natural ligand of TSHR, as the antigen‐binding domain to target TSHR. The TSH‐CAR‐T cells demonstrate effective antitumor activity against TSHR‐positive differentiated thyroid cancer (DTC) cell lines in vitro, accompanied by cytokine release (IFNγ, IL‐2) and robust proliferation. In addition, TSH‐CAR‐T cells achieved complete tumor eradication and sustained remission in two distinct thyroid cancer xenograft models. Furthermore, for comprehensively evaluate the safety profile of TSH‐CAR‐T cell, a murine TSH‐CAR (mTSH‐CAR‐T) is engineered, revealing that mTSH‐CAR‐T cells effectively control mTSHR‐positive tumor growth without evident on‐target/off‐tumor 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‐CAR‐T for patients suffering from metastatic and radioiodine‐resistant DTC.