Ma Tengyun, Xie Yiting, Long Xinyi, Ye Feng
Department of Pathology, Institute of Clinical Pathology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Front Oncol. 2025 Aug 25;15:1644562. doi: 10.3389/fonc.2025.1644562. eCollection 2025.
Despite the generally favorable prognosis of differentiated thyroid carcinoma (DTC) following surgery and radioactive iodine (RAI) therapy, approximately 10% of cases eventually develop resistance to RAI. This condition, known as radioiodine-refractory differentiated thyroid carcinoma (RAIR-DTC), is associated with a poor prognosis, with a 10-year survival rate of only 10% from the time of metastasis detection. The limited availability of safe and effective alternative treatments poses a significant challenge to clinical management. However, early identification and intervention targeting high-risk factors are critical for preventing disease progression. Integrating current insights into DTC pathogenesis with established clinical strategies offers valuable opportunities to inform the development of novel therapies and improve patient outcomes. Hence, in this review, we first examine high-risk predictors of RAIR, including demographic factors (e.g., age, sex), gene mutations (e.g., RAS, BRAF, TERT), high-risk histopathological subtypes (e.g., extrathyroidal extension and the tall cell variant), and serum biomarkers (e.g., thyroglobulin and Cyfra 21.1), all of which are widely recognized for monitoring and risk stratification. Notably, we also emphasize that inappropriate pharmacological management of comorbidities-such as diabetes, myeloid leukemia, and hypertension-may suppress sodium-iodide symporter (NIS) expression and RAI uptake, thereby contributing to RAIR development. We then summarize the molecular mechanisms underlying impaired NIS expression and function in RAIR-DTC, followed by a discussion of recent advances in clinical treatment, focusing on the efficacy and safety of both approved and investigational therapeutic agents.
尽管分化型甲状腺癌（DTC）手术后接受放射性碘（RAI）治疗的总体预后良好，但约10%的病例最终会对RAI产生耐药性。这种情况被称为放射性碘难治性分化型甲状腺癌（RAIR-DTC），其预后较差，从转移检测时起10年生存率仅为10%。安全有效的替代治疗方法有限，给临床管理带来了重大挑战。然而，针对高危因素的早期识别和干预对于预防疾病进展至关重要。将目前对DTC发病机制的认识与既定的临床策略相结合，为开发新疗法和改善患者预后提供了宝贵机会。因此，在本综述中，我们首先研究RAIR的高危预测因素，包括人口统计学因素（如年龄、性别）、基因突变（如RAS、BRAF、TERT）、高危组织病理学亚型（如甲状腺外侵犯和高细胞变体）以及血清生物标志物（如甲状腺球蛋白和细胞角蛋白19片段），所有这些在监测和风险分层中都得到广泛认可。值得注意的是，我们还强调，对合并症（如糖尿病、髓系白血病和高血压）的药物管理不当可能会抑制钠碘同向转运体（NIS）的表达和RAI摄取，从而导致RAIR的发生。然后，我们总结了RAIR-DTC中NIS表达和功能受损的分子机制，接着讨论了临床治疗的最新进展，重点关注已批准和正在研究的治疗药物的疗效和安全性。
