n radioiodide n signal transduction inhibitor n sodium iodide symporter n thyroid cancer More than 60 years of experience of radioiodide therapy has indicated its usefulness for the treatment of differentiated thyroid cancer. This therapy utilizes the differentiated function of thyroid cells, namely iodide uptake for thyroid hormone synthesis. The sodium iodide symporter (NIS) efficiently mediates the iodide uptake in thyroid cells. If functional NIS expression is preserved in metastatic tumors, b-emitting radioiodide-131 (I) is administered after total thyroidectomy, and tumors will concentrate I sufficiently for selective ablation. A total of 30–40% of metastatic diseases, however, do not respond to I therapy [1], mainly due to loss of functional NIS expression [2]. In addition, moderate side effects are still common (10–60%) in NIS-expressing nonthyroidal tissues [3], including sialadenitis and conjunctivitis. Since greater NIS expression in thyroid cancer is associated with more robust I uptake and a better prognosis, enhancement of the native NIS expression has been widely attempted in basic and preclinical research [4]. Attenuation of oncogenic signaling pathways has become a promising approach for expanding the indications and usage of radioiodide therapy to treat resistant tumors.