【摘要】 甲状腺癌（thyroid cancer,TC）是一种常见的内分泌系统恶性肿瘤，其中分化型TC(differentiated TC,DTC)占90%以上，通常大多数患者在接受放射性碘（radioactive iodine,RAI）治疗后总体预后良好，但仍有部分患者的病灶在治疗过程中逐渐丧失摄碘能力，成为RAI难治性DTC(radioiodine-refractory DTC,RAIR-DTC)，预后较差。对于无法手术切除的RAIR-DTC复发病灶或远处转移灶，既往认为治疗方式有限。随着对RAIR-DTC的发生机制及其生物分子层面的改变有了更深的认识，靶向治疗、免疫治疗及靶向治疗联合免疫治疗呈现出广阔的应用前景，其有效性和安全性也在人类研究中被证实，为RAIR-DTC治疗带来新的希望。本文概括了RAIR-DTC的发生、发展机制、靶向治疗与免疫治疗的临床研究现状及其主要结论，以期为今后的研究提供方向。多激酶抑制剂（multiple kinase inhibitors,MKIs）是晚期转移性RAIR-DTC的一线治疗方案。目前被美国食品药品管理局（Food and Drug Administration,FDA）批准用于治疗RAIR-DTC的药物包括索拉非尼（sorafenib）、仑伐替尼（lenvatinib）、卡博替尼（cabozantinib），前两者也被中国国家药品监督管理局批准用于RAIR-DTC的治疗。中国还有安罗替尼（anlotinib）、多纳非尼（donafenib）被批准用于RAIR-DTC的治疗。以上靶向药物的有效性和安全性均得到了验证。阿帕替尼（apatinib）是一种中国自主研发的血管生成抑制剂，有望成为sorafenib耐药时有效的挽救治疗方法。而单靶点选择性抑制剂因作用靶点单一，不良反应通常较轻。对于某些含有特定突变类型的RAIRDTC，单靶点选择性抑制剂可以更好地发挥效果。TC通常被认为肿瘤突变负荷（tumor mutation burden,TMB）较低，既往认为免疫治疗的效果有限。包括帕博利珠单抗（pembrolizumab）、度伐利尤单抗（durvalumab）、阿特珠单抗（atezolizumab）、伊匹单抗（ipilimumab）在内的免疫检查点抑制剂，单独使用时疗效常不理想。当联合靶向治疗时，pembrolizumab可以增强靶向药物的疗效，可作为一种可行的挽救疗法，这可能与靶向治疗联合免疫治疗的“协同效应”有关。对于联合治疗，各种治疗分别对抑制肿瘤、延长患者生存期发挥了多大作用需要明确，特别是在病例数较少的情况下，如何设计合理的对照成为关键。既往研究受限于RAIR-DTC定义模糊、纳入患者量少且异质性大，未来需要开展前瞻性、多中心、大规模的临床试验。同时，还需要考虑治疗后延长的无进展生存期（progression-free survival,PFS）是否能转化为长期生存获益，以及是否能改善患者的生活质量。总之，RAIR-DTC的治疗仍面临诸多挑战，未来需要在这些方面不断探索和研究。更多还原

【Abstract】 Thyroid cancer(TC) is a common malignant tumor of the endocrine system, with differentiated TC(DTC) accounting for more than 90%. Most patients usually have a good overall prognosis after receiving radioactive iodine(RAI) treatment, however some patients’ lesions gradually lose the ability to take up iodine during treatment and become RAI-refractory DTC(RAIR-DTC),with a poor prognosis. For RAIR-DTC recurrence lesions or distant metastases that cannot be surgically removed, it was previously believed that there were limited treatment options. With a deeper understanding of the pathogenesis of RAIR-DTC and its changes at the biomolecular level, targeted therapy, immunotherapy and combined targeted and immune therapy have shown broad application prospects. Their effectiveness and safety have also been confirmed in human studies, bringing new hope for the treatment of RAIRDTC. This article summarized the pathogenesis and development mechanism of RAIR-DTC, the current status of clinical research on targeted therapy and immunotherapy, and their main conclusions, in order to provide direction for future research. Multi-kinase inhibitors(MKIs) are the first-line therapy for advanced metastatic RAIR-DTC. Currently, Food and Drug Administration(FDA) of the United States has approved the following drugs for the treatment of RAIR-DTC: sorafenib, lenvatinib and cabozantinib. The first two of these have been approved by China National Medical Products Administration for RAIR-DTC treatment. In China, anlotinib and donafenib have also been approved for RAIR-DTC treatment. The efficacy and safety of these targeted therapies have been verified. Apatinib, an anti-angiogenesis inhibitor independently developed in China, is expected to be an effective salvage therapy for sorafenib-resistant lesions. Selective single-target inhibitors, with their more specific action targets, generally cause fewer side effects. For certain RAIR-DTC patients with specific mutation types, selective single-target inhibitors may be more effective. TC is generally considered to have a low tumor mutational burden(TMB), and its response to immunotherapy was once thought to be limited. Immune checkpoint inhibitors(ICIs), including pembrolizumab, durvalumab, atezolizumab and ipilimumab, have shown limited efficacy when used alone. However, when combined with targeted therapy, pembrolizumab can enhance the efficacy of targeted drugs, serving as a viable salvage therapy, potentially due to the “synergistic effect” of the combination therapy. It is crucial to determine the individual contributions of each therapy to tumor suppression and survival extension, especially when the sample size is limited. The design of reasonable controls becomes the key in these studies. Previous studies were obstructed by the unclear definition of RAIR-DTC, limited sample sizes and high heterogeneity. Therefore, prospective, multi-center, large-scale clinical trials are needed in the future. Additionally, it is essential to consider whether prolonged progression-free survival(PFS) after treatment can be translated into long-term survival benefits, and whether it improves the quality of life for patients. In conclusion, the treatment of RAIR-DTC still faces many challenges, we must continue to explore and address these issues in the future.更多还原