Abstract
Metastatic differentiated thyroid cancer (DTC) is responsible for most thyroid cancer-related deaths, with an even worse prognosis for patients with radioactive iodine (RAI)-refractory DTC (RAIR-DTC). While multikinase inhibitors (MKIs) and tyrosine kinase inhibitors (TKIs) offer effective treatments for RAIR-DTC, most patients remain noncurative and eventually experience disease progression. In addition, long-term use of these medications is hindered by adverse events, drug resistance and high cost. Recently, the use of MKIs and TKIs has reignited interest in enhancing RAI incorporation. This approach aims to restore the effectiveness of RAI therapy in patients with RAIR-DTC by using agents that increase RAI uptake, potentially overcoming current treatment challenges. This review covers the molecular mechanisms behind RAI resistance, the definition of RAIR-DTC and the efforts to enhance RAI incorporation through various agents, including those currently undergoing clinical trials.