Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapyFeb 22, 2023

Radioiodine Treatment in Advanced Thyroid Cancer: Causes of Resistance and Ways to Overcome It

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 1, 2026

Abstract

Approximately 60% of patients with aggressive metastatic differentiated thyroid cancer develop resistance to radioactive iodine treatment.

Differentiated thyroid cancer (DTC) is the most common subtype of thyroid cancer and is typically treatable with surgery and radioactive iodine therapy.
Resistance to radioactive iodine is linked to factors such as gene mutations, impaired iodine transport into cancer cells, and interactions with the tumor microenvironment.
New biological strategies, including targeted therapies, cell redifferentiation, and improved drug delivery methods, have been developed to enhance radioactive iodine function.
Despite some early successes with these strategies, overall survival rates have not significantly improved for most patients.

Simplified

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.

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Radioiodine Treatment in Advanced Thyroid Cancer: Causes of Resistance and Ways to Overcome It

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