甲状腺免疫相关不良事件在晚期非小细胞肺癌免疫治疗中的临床意义与研究进展
Clinical Significance and Research Progress of Thyroid Immune-Related Adverse Events in Immunotherapy for Advanced Non-Small Cell Lung Cancer
摘要: 免疫检查点抑制剂(ICIs)极大地改善了晚期非小细胞肺癌(NSCLC)的预后，但其引起的甲状腺免疫相关不良事件(thyroid-irAEs)日益受到关注。本文系统综述了thyroid-irAEs的流行病学、发病机制、与疗效的关联，重点探讨其作为疗效预测标志物的潜力与争议。现有证据显示，thyroid-irAEs发生率为15%~40%，以甲减为主；其机制核心是PD-1/PD-L1通路阻断后自身反应性T细胞介导的破坏性甲状腺炎。多项研究证实，发生thyroid-irAEs的患者客观缓解率和生存期显著改善，但该关联存在时间偏倚、因果方向不明等争议。未来需前瞻性研究验证其独立预测价值，并探索机制与遗传风险。将甲状腺功能障碍从副作用转化为疗效预测因子，是实现免疫精准管理的重要方向。
Abstract: Immune checkpoint inhibitors (ICIs) have greatly improved the prognosis of advanced non-small cell lung cancer (NSCLC), yet thyroid immune-related adverse events (thyroid-irAEs) have drawn increasing attention. This article systematically reviews the epidemiology, pathogenesis, and association with therapeutic efficacy of thyroid-irAEs, with a focus on the potential and controversy surrounding their role as predictive biomarkers of response. Current evidence indicates that the incidence of thyroid-irAEs ranges from 15% to 40%, with hypothyroidism being the predominant manifestation. The core mechanism involves destructive thyroiditis mediated by autoreactive T cells following blockade of the PD-1/PD-L1 pathway. Multiple studies have confirmed that patients who develop thyroid-associated immune-related adverse events (thyroid-irAEs) show significantly improved objective response rates and survival outcomes. However, this association remains debated due to issues such as time bias and unclear causal direction. Future prospective studies are needed to validate the independent predictive value of thyroid-irAEs and to explore their underlying mechanisms and genetic risk factors. Translating thyroid dysfunction from an adverse event into a predictor of efficacy represents a crucial direction for achieving precision immuno-oncology management.
文章引用：龚家玮, 吴元磊, 卢华, 彭中一, 李巍. 甲状腺免疫相关不良事件在晚期非小细胞肺癌免疫治疗中的临床意义与研究进展[J]. 临床医学进展, 2026, 16(7): 422-429. https://doi.org/10.12677/acm.2026.1672542

参考文献

[1] Bray, F., Laversanne, M., Sung, H., Ferlay, J., Siegel, R.L., Soerjomataram, I., et al. (2024) Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 74, 229-263. [Google Scholar] [CrossRef] [PubMed]
[2] Reck, M., Rodríguez-Abreu, D., Robinson, A.G., Hui, R., Csőszi, T., Fülöp, A., et al. (2019) Updated Analysis of KEYNOTE-024: Pembrolizumab versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer with PD-L1 Tumor Proportion Score of 50% or Greater. Journal of Clinical Oncology, 37, 537-546. [Google Scholar] [CrossRef] [PubMed]
[3] George, A.S., Fernandez, C.J., Eapen, D. and Pappachan, J.M. (2021) Organ-Specific Adverse Events of Immune Checkpoint Inhibitor Therapy, with Special Reference to Endocrinopathies. TouchREVIEWS in Endocrinology, 17, 21-32. [Google Scholar] [CrossRef] [PubMed]
[4] Wu, L., Xu, Y., Wang, X., Cheng, X., Zhang, Y., Wang, Y., et al. (2023) Thyroid Dysfunction after Immune Checkpoint Inhibitor Treatment in a Single-Center Chinese Cohort: A Retrospective Study. Endocrine, 81, 123-133. [Google Scholar] [CrossRef] [PubMed]
[5] Muir, C.A., Clifton-Bligh, R.J., Long, G.V., Scolyer, R.A., Lo, S.N., Carlino, M.S., et al. (2021) Thyroid Immune-Related Adverse Events Following Immune Checkpoint Inhibitor Treatment. The Journal of Clinical Endocrinology & Metabolism, 106, e3704-e3713. [Google Scholar] [CrossRef] [PubMed]
[6] Wang, L., Han, Y., Wu, T., et al. (2025) Incidence and Risk Assessment of Thyroid Dysfunction Following Immune Checkpoint Inhibitor Therapy: A Systematic Review and Meta-Analysis. American Journal of Translational Research, 17, 9259-9274. [Google Scholar] [CrossRef] 
[7] Liu, Y., Zhang, J., Yang, L., Gan, J., Zhang, H., Qi, Q., et al. (2025) Endocrine Immune-Related Adverse Events in Advanced Lung Cancer Patients Receiving Immune Checkpoint Inhibitors: Incidence, Predictors and Outcomes. Translational Lung Cancer Research, 14, 5393-5404. [Google Scholar] [CrossRef] 
[8] Quan, L., Liu, J., Wang, Y., Yang, F., Yang, Z., Ju, J., et al. (2024) Exploring Risk Factors for Endocrine-Related Immune-Related Adverse Events: Insights from Meta-Analysis and Mendelian Randomization. Human Vaccines & Immunotherapeutics, 20, Article ID: 2410557. [Google Scholar] [CrossRef] [PubMed]
[9] Chieng, J.H.L., Htet, Z.W., Zhao, J.J., Tai, E.S., Tay, S.H., Huang, Y., et al. (2022) Clinical Presentation of Immune-Related Endocrine Adverse Events during Immune Checkpoint Inhibitor Treatment. Cancers, 14, Article No. 2687. [Google Scholar] [CrossRef] [PubMed]
[10] Ide, N., Tsuruta, Y., Sako, K. and Maeda, T. (2026) Sex Differences in Thyroid Dysfunction Onset Timing Induced by Immune Checkpoint Inhibitors: JADER Disproportionality Analysis. Expert Opinion on Drug Safety, 1-8. [Google Scholar] [CrossRef] 
[11] Zhan, L., Feng, H.F., Liu, H.Q., Guo, L., Chen, C., Yao, X., et al. (2021) Immune Checkpoint Inhibitors-Related Thyroid Dysfunction: Epidemiology, Clinical Presentation, Possible Pathogenesis, and Management. Frontiers in Endocrinology, 12, Article ID: 649863. [Google Scholar] [CrossRef] [PubMed]
[12] Chera, A., Stancu, A.L. and Bucur, O. (2022) Thyroid-Related Adverse Events Induced by Immune Checkpoint Inhibitors. Frontiers in Endocrinology, 13, Article ID: 1010279. [Google Scholar] [CrossRef] [PubMed]
[13] Karaviti, D., Kani, E., Karaviti, E., Gerontiti, E., Michalopoulou, O., Stefanaki, K., et al. (2024) Thyroid Disorders Induced by Immune Checkpoint Inhibitors. Endocrine, 85, 67-79. [Google Scholar] [CrossRef] [PubMed]
[14] Lechner, M.G., Zhou, Z., Hoang, A.T., Huang, N., Ortega, J., Scott, L.N., et al. (2023) Clonally Expanded, Thyrotoxic Effector CD8+ T Cells Driven by IL-21 Contribute to Checkpoint Inhibitor Thyroiditis. Science Translational Medicine, 15, eadg0675. [Google Scholar] [CrossRef] [PubMed]
[15] Schönberger, E., Švitek, L., Grubišić, B., Cvijić Perić, T., Marušić, R., Vlahović Vlašić, N., et al. (2025) Beyond Tumor Immunity: The Disruption of Endocrine and Infectious Homeostasis by Immune Checkpoint Inhibitors. International Journal of Molecular Sciences, 26, Article No. 11619. [Google Scholar] [CrossRef] 
[16] Yamauchi, I., Sakane, Y., Fukuda, Y., Fujii, T., Taura, D., Hirata, M., et al. (2017) Clinical Features of Nivolumab-Induced Thyroiditis: A Case Series Study. Thyroid®, 27, 894-901. [Google Scholar] [CrossRef] [PubMed]
[17] Kotwal, A., Gustafson, M.P., Bornschlegl, S., Kottschade, L., Delivanis, D.A., Dietz, A.B., et al. (2020) Immune Checkpoint Inhibitor-Induced Thyroiditis Is Associated with Increased Intrathyroidal T Lymphocyte Subpopulations. Thyroid®, 30, 1440-1450. [Google Scholar] [CrossRef] [PubMed]
[18] Yasuda, Y., Iwama, S., Sugiyama, D., Okuji, T., Kobayashi, T., Ito, M., et al. (2021) CD4+ T Cells Are Essential for the Development of Destructive Thyroiditis Induced by Anti-PD-1 Antibody in Thyroglobulin-Immunized Mice. Science Translational Medicine, 13, eabb7495. [Google Scholar] [CrossRef] [PubMed]
[19] Wrońska, K., Hałasa, M. and Szczuko, M. (2024) The Role of the Immune System in the Course of Hashimoto’s Thyroiditis: The Current State of Knowledge. International Journal of Molecular Sciences, 25, Article No. 6883. [Google Scholar] [CrossRef] [PubMed]
[20] Mao, X., Mao, C., Liu, J., Wang, X. and Mao, Y. (2025) Immune Checkpoint Inhibitor-Induced Thyroiditis and Its Potential Mechanisms. Frontiers in Endocrinology, 16, Article ID: 1584675. [Google Scholar] [CrossRef] [PubMed]
[21] Martin, T.C., Ilieva, K.M., Visconti, A., Beaumont, M., Kiddle, S.J., Dobson, R.J.B., et al. (2020) Dysregulated Antibody, Natural Killer Cell and Immune Mediator Profiles in Autoimmune Thyroid Diseases. Cells, 9, Article No. 665. [Google Scholar] [CrossRef] [PubMed]
[22] Jiao, Y., Xu, M. and Rao, X. (2025) Correlation between Different Levels of Thyroid Autoantibodies and Immune Checkpoint Inhibitor-Associated Thyroid Dysfunction. Frontiers in Endocrinology, 16, Article ID: 1620718. [Google Scholar] [CrossRef] 
[23] Rajan, R. and Nandakumar, D. (2025) Endocrine Adverse Events of Immune Checkpoint Inhibitors: A Comprehensive Review. Indian Journal of Endocrinology and Metabolism, 29, 408-413. [Google Scholar] [CrossRef] 
[24] Percik, R., Criseno, S., Adam, S., Young, K. and Morganstein, D.L. (2023) Diagnostic Criteria and Proposed Management of Immune-Related Endocrinopathies Following Immune Checkpoint Inhibitor Therapy for Cancer. Endocrine Connections, 12, e220513. [Google Scholar] [CrossRef] [PubMed]
[25] Li, Z., Xia, Y., Xia, M., Liu, C., Wang, T., Liu, Y., et al. (2023) Immune-Related Thyroid Dysfunction Is Associated with Improved Long-Term Prognosis in Patients with Non-Small Cell Lung Cancer Treated with Immunotherapy: A Systematic Review and Meta-Analysis. Journal of Thoracic Disease, 15, 690-700. [Google Scholar] [CrossRef] [PubMed]
[26] Wang, Y., Ma, X., Ma, J., Li, J., Lin, Z., Gao, W., et al. (2025) Thyroid Dysfunction as a Predictor of PD-1/PD-L1 Inhibitor Efficacy in Advanced Lung Cancer. BMC Cancer, 25, Article No. 791. [Google Scholar] [CrossRef] [PubMed]
[27] Dong, Y., Li, Y., Peng, X. and Fang, W. (2026) Immune Checkpoint Inhibitors-Induced Thyroid Dysfunction Improves the Prognosis of Patients with Lung Cancer: A Meta-Analysis and Systematic Review. Frontiers in Endocrinology, 16, Article ID: 1743245. https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2025.1743245/full [Google Scholar] [CrossRef] 
[28] García-Goñi, M., Vázquez Gutiérrez, B., Sanmamed, M.F., Martín-Algarra, S., Luis Pérez-Gracia, J., Olmedo, M., et al. (2024) Thyroid Dysfunction Caused by Immune Checkpoint Inhibitors Improves Cancer Outcomes. Endocrine-Related Cancer, 31, e240064. [Google Scholar] [CrossRef] [PubMed]
[29] Guo, G., Jing, Z., Dou, W., Wang, G., Dang, J., Li, Y., et al. (2024) Immune-Related Thyroid Dysfunction as a Positive Prognostic Factor for Patients with Lung Cancer in China: A Real-World Retrospective Study. Frontiers in Immunology, 15, Article ID: 1495460. [Google Scholar] [CrossRef] [PubMed]
[30] Iwama, S., Kobayashi, T. and Arima, H. (2025) Management, Biomarkers and Prognosis in People Developing Endocrinopathies Associated with Immune Checkpoint Inhibitors. Nature Reviews Endocrinology, 21, 289-300. [Google Scholar] [CrossRef] [PubMed]

为你推荐