From bench to bedside: the evolving role of iodine in thyroid cancer management

Iodine metabolism has a central role in thyroid physiology and thyroid cancer biology, shaping both tumour behaviour and therapeutic strategies. Within the past 20 years, advancements in molecular research and targeted therapies have transformed the understanding of iodine metabolism in thyroid cancer and subsequently changed clinical management. In differentiated thyroid carcinomas, the ability of tumour cells to concentrate iodide provides the biological foundation of radioactive iodine treatment. However, loss of iodide-handling machinery function drives refractoriness in advanced disease, posing a major clinical challenge. Molecular genetics has now been integrated into routine clinical practice and genetically guided strategies to restore iodine uptake in previously non-avid lesions have emerged. This Review synthesizes these breakthroughs across molecular science, pathology, physics and clinical practice. We describe emerging predictive markers of radioiodine-refractory disease and summarize the current state of knowledge on iodide-handling mechanisms, their dysregulation in thyroid tumourigenesis and therapeutic advances made in the past 15 years aimed at redifferentiation. By bridging molecular insights with translational and clinical perspectives, we aim to highlight evolving paradigms that promise to refine patient stratification and improve outcomes in differentiated thyroid carcinoma.