Not all cancers respond to radioactive iodine because the effectiveness of this treatment depends on the cancer cells’ ability to absorb iodine, which varies widely among different cancer types and even among subtypes of the same cancer. Radioactive iodine therapy primarily works by exploiting the natural iodine uptake mechanism of thyroid cells. The thyroid gland uniquely concentrates iodine from the bloodstream using a specialized protein called the sodium-iodide symporter (NIS). This allows radioactive iodine, such as iodine-131, to enter thyroid cells and deliver targeted radiation that kills them. Consequently, cancers derived from thyroid cells, especially differentiated thyroid cancers, often respond well to radioactive iodine because they retain this iodine-absorbing ability.
However, many cancers do not have this iodine uptake mechanism. Non-thyroid cancers generally lack the sodium-iodide symporter or do not express it at sufficient levels, so radioactive iodine cannot selectively enter and destroy those cancer cells. Even within thyroid cancers, some tumors lose the ability to absorb iodine over time or never had it strongly to begin with. This phenomenon is known as radioactive iodine-refractory differentiated thyroid carcinoma (RAIR-DTC). In these cases, the cancer cells either reduce or lose NIS expression or have molecular changes that impair iodine uptake and retention, making radioactive iodine therapy ineffective.
Several factors contribute to why some thyroid cancers become refractory to radioactive iodine:
– **Molecular and genetic changes:** Mutations in genes such as BRAF, RAS, and TERT promoter are associated with reduced NIS expression and function. These mutations alter the cancer cells’ biology, leading to decreased iodine uptake.
– **Tumor differentiation:** Well-differentiated thyroid cancers resemble normal thyroid tissue and usually retain iodine uptake ability. Poorly differentiated or undifferentiated thyroid cancers lose this characteristic, making them less responsive.
– **Histopathological features:** Certain aggressive subtypes, like the tall cell variant, are more likely to be refractory.
– **Tumor environment and progression:** As tumors grow and metastasize, they may lose iodine uptake capacity.
– **Pharmacological and systemic factors:** Some medications and comorbid conditions can suppress NIS expression or function, further reducing iodine uptake.
Because radioactive iodine therapy relies on the cancer cells’ ability to concentrate iodine, if that mechanism is absent or impaired, the treatment cannot deliver its radioactive payload effectively. This limits its use primarily to thyroid cancers that maintain this function. For other cancers, or for thyroid cancers that become refractory, alternative treatments such as surgery, external radiation, targeted therapies, or chemotherapy are necessary.
In summary, the key reason not all cancers respond to radioactive iodine is that most cancers do not have the biological machinery to absorb iodine, and even among thyroid cancers, changes in tumor biology can lead to loss of this ability, rendering radioactive iodine therapy ineffective.
