Thyroid cancer, particularly differentiated thyroid cancer (DTC), represents the most prevalent endocrine malignancy, with a rising incidence globally. Although radioactive iodine (RAI) therapy remains a cornerstone for DTC management, the emergence of radioactive iodine-refractory (RAIR) disease poses a significant challenge and is associated with a worse prognosis. Recent advances in molecular biology have elucidated the complex mutational landscape underlying thyroid cancer pathogenesis and its significant impact on RAI sensitivity. This comprehensive review systematically explores the common genetic alterations in DTC, including B-Raf proto-oncogene, serine/threonine kinase ( BRAF ) and RAS mutations, rearranged during transfection (RET)/ PTC rearrangements, and telomerase reverse transcriptase ( TERT )-promoter mutations, along with other related variations, and their plausible molecular mechanisms influencing iodine uptake and cellular differentiation. The synergistic effects of co-mutations, such as BRAF V600E combined with TERT -promoter mutations and PIK3CA alterations, collectively promote dedifferentiation and RAI resistance by downregulating the sodium-iodide symporter (NIS) and inducing hyperactivation of oncogenic signaling pathways. Furthermore, this article critically evaluates the clinical utility of these genetic markers as predictors of response to RAI therapy and prognostic indicators, highlighting their evolving role in risk stratification and personalized treatment strategies. Finally, this review provides an in-depth analysis of emerging redifferentiation therapies, including mitogen-activated protein kinase (MAPK) pathway inhibitors, RET inhibitors, neurotrophin receptor kinase (NTRK) inhibitors, and other related agents. These therapies have demonstrated promising results in restoring iodine avidity in RAIR tumors, thereby enabling subsequent effective RAI administration. This review aims to synthesize current knowledge and provide clinical insights to optimize thyroid cancer management through a precision medicine approach.
Wu et al. (Wed,) studied this question.