Radioiodine therapy in advanced differentiated thyroid cancer: Resistance and overcoming strategy

Drug Resist Updat. 2023 May:68:100939. doi: 10.1016/j.drup.2023.100939. Epub 2023 Feb 8.


Thyroid cancer is the most prevalent endocrine tumor and its incidence is fast-growing worldwide in recent years. Differentiated thyroid cancer (DTC) is the most common pathological subtype which is typically curable with surgery and Radioactive iodine (RAI) therapy (approximately 85%). Radioactive iodine is the first-line treatment for patients with metastatic Papillary Thyroid Cancer (PTC). However, 60% of patients with aggressive metastasis DTC developed resistance to RAI treatment and had a poor overall prognosis. The molecular mechanisms of RAI resistance include gene mutation and fusion, failure to transport RAI into the DTC cells, and interference with the tumor microenvironment (TME). However, it is unclear whether the above are the main drivers of the inability of patients with DTC to benefit from iodine therapy. With the development of new biological technologies, strategies that bolster RAI function include TKI-targeted therapy, DTC cell redifferentiation, and improved drug delivery via extracellular vesicles (EVs) have emerged. Despite some promising data and early success, overall survival was not prolonged in the majority of patients, and the disease continued to progress. It is still necessary to understand the genetic landscape and signaling pathways leading to iodine resistance and enhance the effectiveness and safety of the RAI sensitization approach. This review will summarize the mechanisms of RAI resistance, predictive biomarkers of RAI resistance, and the current RAI sensitization strategies.

Keywords: Advanced differentiated thyroid cancer; Molecular mechanisms; Radioiodine (RAI) resistance; Sodium iodide symporter (NIS); Tyrosine kinase inhibitors (TKIs).

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers
  • Humans
  • Iodine Radioisotopes / therapeutic use
  • Signal Transduction
  • Thyroid Neoplasms* / drug therapy
  • Thyroid Neoplasms* / genetics
  • Thyroid Neoplasms* / radiotherapy
  • Tumor Microenvironment / genetics


  • Iodine Radioisotopes
  • Biomarkers