Antigen loss remains a major barrier to chimeric antigen receptor (CAR) T cell efficacy in solid tumors. In aggressive thyroid cancers, dedifferentiation is accompanied by coordinated loss of lineage-restricted surface antigens, limiting immune recognition.

Thyroid-stimulating hormone receptor (TSHR) expression was assessed on multiple histotypes of thyroid cancer via immunohistochemistry. TSHR-directed chimeric antigen receptor T (CART) cell therapy was assessed against differentiated thyroid cancer subtypes which highly expressed TSHR and dedifferentiated thyroid cancer subtypes which downregulated TSHR in vitro and in xenograft and patient-derived xenograft (PDX) mouse models. MAPK inhibitors were assessed in combination with TSHR-CART cell therapy in dedifferentiated thyroid cancers which downregulated TSHR in vitro and in PDX mouse models.

Using TSHR as a clinically relevant antigen target, we demonstrated that pharmacologic tumor redifferentiation can restore target expression and sensitize tumors to CART cell therapy. TSHR-CART cells mediate durable antigen-specific cytotoxicity in TSHRhigh differentiated thyroid cancer models but are limited in TSHRlow dedifferentiated tumors. In patient-derived anaplastic thyroid cancer xenografts, MAPK inhibition restores TSHR expression and converts tumors from CAR-resistant to CAR-responsive. Concurrent redifferentiation therapy and CART cell treatment yields superior tumor control and survival versus monotherapy, without impairing CART cell function.

These findings establish tumor redifferentiation as a generalizable strategy to overcome antigen loss and enhance CART cell therapy in thyroid cancer and potentially other solid tumors.