Sunitinib enhances cuproptosis induced by copper ionophores via ROS-ATF3-SLC31A1 axis in thyroid Carcinoma.

The clinical management of advanced thyroid carcinoma presents substantial therapeutic challenges due to non-curative surgical outcomes and resistance to both radioiodine therapy and conventional chemotherapeutic agents. Emerging evidence implicates copper dysregulation in thyroid cancer pathogenesis, yet monotherapy with copper ionophores demonstrates constrained efficacy due to tumor-intrinsic adaptive resistance mechanisms. In this study, we investigated the therapeutic potential of combining Sunitinib with copper ionophore Elesclomol as a novel strategy against thyroid carcinoma. Mechanically, we identified that Sunitinib treatment induces ROS accumulation, activating the stress-responsive transcription factor ATF3, which directly binds and transactivates the copper transporter gene SLC31A1. Clinically, TCGA analysis reveals SLC31A1 as a vulnerability in advanced thyroid cancer, with expression significantly downregulated in metastatic lesions, a deficit rescued by Sunitinib. Overall, these results demonstrate that Sunitinib and copper ionophores can induce synergistic cytotoxic effect, shedding light on therapeutic strategy for advanced thyroid carcinomas.