Abstract:

Radioiodine-refractory thyroid cancer (RAIR-TC) refers to thyroid cancer that is unable to or difficult to benefit from ¹³¹I treatment. The type of RAIR-TC we commonly encounter is differentiated thyroid cancer (DTC), which is originally well-differentiated but gradually loses its ability to take up iodine during disease progression or after ¹³¹I treatment. Compared to DTC that can still take up ¹³¹I, RAIR-TC is more malignant, progresses more rapidly, and carries a higher risk of death. Therefore, the subsequent treatment of RAIR-TC has become a hotspot and a challenge in the field of international thyroid cancer research. The treatment of RAIR-TC has evolved through several stages, from initial radioactive iodine therapy to the introduction of targeted drugs in recent years, followed by attempts at immunotherapy, diversifying treatment options. Molecular targeted therapy, especially tyrosine kinase inhibitors (TKIs), has provided new treatment choices for RAIR-TC patients. However, resistance to single-agent targeted therapy has quickly emerged as a bottleneck in treatment efficacy. Studies have shown that the activation of the phosphoinositide3-kinase (PI3K)/protein kinase (AKT)/mammalian target of rapamycin (mTOR) pathway and epidermal growth factor receptor (EGFR) pathway is the main mechanism by which tumors evade targeted therapy. As a result, combination therapy strategies have emerged, aiming to target multiple signaling pathways and optimize the use of combined drugs to overcome single-drug resistance. Additionally, designing personalized treatment plans based on patients’ molecular features (such as BRAF mutations and tumor immune phenotypes) has become a research focus. Immunotherapy, especially immune checkpoint inhibitors (ICIs) such as pembrolizumab, has shown some clinical effect in RAIR-TC patients with high level of programmed death ligand-1 (PD-L1) expression. However, due to the low immunogenicity of RAIR-TC, the overall response rate to immunotherapy remains relatively low, typically ranging from 10% to 15%. In recent years, combination strategies involving targeted therapy and immunotherapy, such as the triplet therapy of BRAF inhibitors, vascular endothelial growth factor receptor (VEGFR) inhibitors, and programmed death-1 (PD-1) inhibitors, have shown significant efficacy in some patients, even achieving complete remission. This offers new directions for improving the efficacy of immunotherapy, however optimizing combination therapy, overcoming resistance, and managing side effects remain key challenges for future research. Moreover, epigenetics and metabolism studies have provided new insights into the treatment of RAIR-TC. Research has shown that epigenetic mechanisms, such as DNA methylation and histone deacetylation, play important roles in the progression and resistance of RAIR-TC. Inhibitors targeting these mechanisms may restore the ability of tumor to take up radioactive iodine, thus enhancing sensitivity to ¹³¹I therapy. Although progress has been made in epigenetic research, clinical trials are still in the early stages, and further verification of their potential is needed. Tumor metabolic abnormalities, particularly changes in lactate and glutamine metabolism, play crucial roles in tumor growth and resistance. Studies have found that glutamine synthetase (GLS) inhibitors and lactate dehydrogenase A (LDHA) inhibitors can effectively suppress tumor growth and potentially reverse resistance. Thus, the development of innovative drugs targeting these metabolic pathways is becoming an important direction for future RAIR-TC treatments. Although current therapies have improved the survival of RAIR-TC patients to some extent, challenges such as resistance, toxic reactions and tumor heterogeneity remain. Future research should focus on optimizing combination treatment strategies, developing new targeted drugs, and improving the adaptability of immunotherapy in clinical trials. With the advancement of multidisciplinary collaboration and technological innovation, breakthroughs in RAIR-TC treatment are expected in the future, ultimately improving patient prognosis and quality of life.

Key words: Radioiodine-refractory thyroid cancer, Precision medicine, Molecular targeted therapy, Immunotherapy, Internal radiation therapy