CAR-T疗法在未分化甲状腺癌中靶点探索的研究进展

doi:10.19803/j.1672-8629.20250551

摘要/Abstract

摘要： 目的探讨嵌合抗原受体T细胞（Chimeric Antigen Receptor T-cell, CAR-T）疗法在未分化甲状腺癌（Anaplastic Thyroid Cancer, ATC）治疗中的靶点研究与应用进展。方法综合分析近年来国内外关于CAR-T疗法在ATC中的研究,归纳其主要靶点（如ICAM-1、TSHR、CSPG4、B7-H3、ROR1等）及作用机制,并分析其临床应用中的关键问题。结果 CAR-T可通过靶向多种ATC相关抗原发挥抗肿瘤作用,但治疗仍受到肿瘤异质性、免疫抑制微环境及安全风险等因素限制。结论深入开展ATC相关抗原的探索与CAR结构优化,结合联合治疗策略,有望提升CAR-T疗法的治疗效能,为ATC的精准免疫治疗提供新的方向与理论基础。

关键词: 未分化甲状腺癌, 嵌合抗原受体T细胞（CAR-T）, 免疫治疗

Abstract: Objective To explore the advances in targets and applications of chimeric antigen receptor T-cell (CAR-T) therapy in the treatment of anaplastic thyroid cancer (ATC). Methods Recent literature on studies on CAR-T therapy in anaplastic thyroid cancer (ATC) was retrieved to summarize the principal therapeutic targets, such as ICAM-1, TSHR, CSPG4, B7-H3, and ROR1, and their underlying mechanisms of action, and to identify major problems encountered in clinical applications. Results CAR-T cells exerted antitumor activity by targeting multiple ATC-associated antigens. However, their therapeutic efficacy was still limited by such factors as tumor heterogeneity, immunosuppressive tumor microenvironments, and potential safety concerns. Conclusion Insights into ATC-associated antigens and optimization of CAR design, in combination with integrated therapeutic strategies, may enhance the efficacy of CAR-T therapy and offer clues to precision immunotherapy in ATC.

Key words: Anaplastic Thyroid Cancer, Chimeric Antigen Receptor T-Cell (CAR-T), Immunotherapy

中图分类号:

R979.1

刘艳琳, 白怀茜, 李志刚, 戴晓雁, 王娟. CAR-T疗法在未分化甲状腺癌中靶点探索的研究进展[J]. 中国药物警戒, 2026, 23(3): 349-354.

LIU Yanlin, BAI Huaixi, LI Zhigang, DAI Xiaoyan, WANG Juan. Research Progress in Target Exploration of CAR-T Therapy for Anaplastic Thyroid Cancer[J]. Chinese Journal of Pharmacovigilance, 2026, 23(3): 349-354.

导出引用管理器 EndNote|Ris|BibTeX

链接本文: https://zgywjj.magtechjournal.com/CN/10.19803/j.1672-8629.20250551

https://zgywjj.magtechjournal.com/CN/Y2026/V23/I3/349

参考文献

[1] BRAY F, LAVERSANNE M, SUNG H, et al.Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263.
[2] PAVLIDIS ET, GALANIS IN, PAVLIDIS TE.Update on Current Diagnosis and Management of Anaplastic Thyroid Carcinoma[J]. World J Clin Oncol, 2023, 14(12): 570-583.
[3] LUONG A, POEI D, CHOW L, et al.Impact of Modern Systemic Therapies on Survival in Patients with Anaplastic Thyroid Cancer: a Single-Center Retrospective Cohort Review[J]. Drugs Real World Outcomes, 2025, 12(2): 295-300.
[4] WU SS, LAMARRE ED, YALAMANCHALI A, et al.Association of Treatment Strategies and Tumor Characteristics with Overall Survival among Patients with Anaplastic Thyroid Cancer: a Single-Institution 21-Year Experience[J]. JAMA Otolaryngol Head Neck Surg, 2023, 149(4): 300-309.
[5] JANNIN A, ESCANDE A, AL GHUZLAN A, et al.Anaplastic Thyroid Carcinoma: an Update[J]. Cancers (Basel), 2022, 14(4): 1061.
[6] TUNIO MA, HINDER D, EMERY B, et al.Modern Therapeutic Approaches in Anaplastic Thyroid Cancer: a Meta-Analytic Review of Randomised and Single Arm Studies on Efficacy and Survival[J]. Cancers (Basel), 2025, 17(5): 777.
[7] SUN Z, WANG C, ZHAO Y, et al.CAR-T Cell Therapy in Advanced Thyroid Cancer: from Basic to Clinical[J]. Front Immunol, 2024, 15: 1411300.
[8] GROSS G, WAKS T, ESHHAR Z.Expression of Immunoglobulin-T-Cell Receptor Chimeric Molecules as Functional Receptors with Antibody-Type Specificity[J]. Proc Natl Acad Sci USA, 1989, 86(24): 10024-10028.
[9] LABANIEH L, MACKALL CL.CAR Immune Cells: Design Principles, Resistance and the Next Generation[J]. Nature, 2023, 614(7949): 635-648.
[10] SADELAIN M, BRENTJENS R, RIVIÈRE I. The Basic Principles of Chimeric Antigen Receptor Design[J]. Cancer Discov, 2013, 3(4): 388-398.
[11] MILONE MC, BHOJ VG.The Pharmacology of T Cell Therapies[J]. Mol Ther Methods Clin Dev, 2018, 8: 210-221.
[12] ZHONG XS, MATSUSHITA M, PLOTKIN J, et al.Chimeric Antigen Receptors Combining 4-1BB and CD28 Signaling Domains Augment PI3kinase/AKT/Bcl-XL Activation and CD8+ T Cell-Mediated Tumor Eradication[J]. Mol Ther, 2010, 18(2): 413-420.
[13] CHMIELEWSKI M, ABKEN H.TRUCKs: the Fourth Generation of CARs[J]. Expert Opin Biol Ther, 2015, 15(8): 1145-1154.
[14] KAGOYA Y, TANAKA S, GUO T, et al.A Novel Chimeric Antigen Receptor Containing a JAK-STAT Signaling Domain Mediates Superior Antitumor Effects[J]. Nat Med, 2018, 24(3): 352-359.
[15] MULLARD A.FDA Approves First CAR T Therapy[J]. Nat Rev Drug Discov, 2017, 16(10): 669.
[16] SMALLRIDGE RC, MARLOW LA, COPLAND JA.Anaplastic Thyroid Cancer: Molecular Pathogenesis and Emerging Therapies[J]. Endocr Relat Cancer, 2009, 16(1): 17-44.
[17] KIMURA T, DOOLITTLE WKL, KRUHLAK M, et al.Inhibition of MEK Signaling Attenuates Cancer Stem Cell Activity in Anaplastic Thyroid Cancer[J]. Thyroid, 2024, 34(4): 484-495.
[18] RUAN X, TAO M, DONG Y, et al.Persistent Pre-Exhausted CD8+ T Cells Shape the Tumor Immune Microenvironment in Anaplastic Thyroid Cancer[J]. Endocr Relat Cancer, 2025, 32(3): e240169.
[19] FRENCH JD, HAUGEN BR.Thyroid Cancer: CAR T Cell Therapy-Potential in Advanced Thyroid Cancer?[J]. Nat Rev Endocrinol, 2018, 14(1): 10-11.
[20] WIRTH LJ, BROSE MS, SHERMAN EJ, et al.Open-Label, Single-Arm, Multicenter, Phase II Trial of Lenvatinib for the Treatment of Patients with Anaplastic Thyroid Cancer[J]. J Clin Oncol, 2021, 39(21): 2359-2366.
[21] YAMAZAKI H, YOKOSE T, HAYASHI H, et al.Expression of Fibroblast Growth Factor Receptor 4 and Clinical Response to Lenvatinib in Patients with Anaplastic Thyroid Carcinoma: a Pilot Study[J]. Eur J Clin Pharmacol, 2020, 76(5): 703-709.
[22] HUANG P, TANG N, MAO LF, et al.Nanoclay Drug-Delivery System Loading Potassium Iodide Promotes Endocytosis and Targeted Therapy in Anaplastic Thyroid Cancer[J]. Nano Lett, 2023, 23(17): 8013-8021.
[23] HAYDINGER CD, ASHANDER LM, TAN ACR, et al.Intercellular Adhesion Molecule 1: More than a Leukocyte Adhesion Molecule[J]. Biology (Basel), 2023, 12(5): 743.
[24] QIU Z, WANG Y, ZHANG Z, et al.Roles of Intercellular Cell Adhesion Molecule-1 (ICAM-1) in Colorectal Cancer: Expression, Functions, Prognosis, Tumorigenesis, Polymorphisms and Therapeutic Implications[J]. Front Oncol, 2022, 12: 1052672.
[25] BUI TM, WIESOLEK HL, SUMAGIN R.ICAM-1: a Master Regulator of Cellular Responses in Inflammation, Injury Resolution, and Tumorigenesis[J]. J Leukoc Biol, 2020, 108(3): 787-799.
[26] MIN IM, SHEVLIN E, VEDVYAS Y, et al.CAR T Therapy Targeting ICAM-1 Eliminates Advanced Human Thyroid Tumors[J]. Clin Cancer Res, 2017, 23(24): 7569-7583.
[27] VEDVYAS Y, MCCLOSKEY JE, YANG Y, et al.Manufacturing and Preclinical Validation of CAR T Cells Targeting ICAM-1 for Advanced Thyroid Cancer Therapy[J]. Sci Rep, 2019, 9(1): 10634.
[28] SROUR SA, LORCH JH, ZAFEREO ME, et al. ICAM-1 Directed Chimeric Antigen Receptor (CAR) T Cells (AIC100) in Patients with Advanced Thyroid Cancers: Clinical and Translational Data from the Phase 1 Dose Escalation Study[J]. Cancer Research, 2025, 85(Suppl 8): CT206.
[29] LI H, ZHOU X, WANG G, et al.CAR-T Cells Targeting TSHR Demonstrate Safety and Potent Preclinical Activity Against Differentiated Thyroid Cancer[J]. J Clin Endocrinol Metab, 2022, 107(4): 1110-1126.
[30] ZHANG J, ZHENG S, XIE R, et al.Epigenetic Control in Thyroid Cancer: Mechanisms and Clinical Perspective[J]. Cell Death Discov, 2025, 11(1): 387.
[31] OISHI N, VUONG H G, MOCHIZUKI K, et al.Loss of 5-Hydroxy-methylcytosine is an Epigenetic Hallmark of Thyroid Carcinomas with TERT Promoter Mutations[J]. Endocr Pathol, 2020, 31(4): 359-366.
[32] PAN Z, LU X, XU T, et al.Epigenetic Inhibition of CTCF by HN1 Promotes Dedifferentiation and Stemness of Anaplastic Thyroid Cancer[J]. Cancer Lett, 2024, 580: 216496.
[33] SAQCENA M, LEANDRO-GARCIA LJ, MAAG JLV, et al.SWI/SNF Complex Mutations Promote Thyroid Tumor Progression and Insensitivity to Redifferentiation Therapies[J]. Cancer Discov, 2021, 11(5): 1158-1175.
[34] DING J, LI D, LIU X, et al.Chimeric Antigen Receptor T-Cell Therapy for Relapsed and Refractory Thyroid Cancer[J]. Exp Hematol Oncol, 2022, 11(1): 59.
[35] ROMAN CM, SIEGLER E, DEMIRER AA, et al.Optimization of TSHR-CART Cell Therapy to Translate into a First in Human Phase I Clinical Trial in Metastatic Thyroid Cancers[J]. Cytotherapy, 2024, 26(Suppl 6): S182-S183.
[36] DU H, HIRABAYASHI K, AHN S, et al. Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells[J]. Cancer Cell, 2019, 35(2): 221-237.e8.
[37] WANG K, OSEI-HWEDIEH DO, WALHART TA, et al.B7-H3 CAR-T Cell Therapy Combined with Irradiation is Effective in Targeting Bulk and Radiation-Resistant Chordoma Cancer Cells[J]. J Immunother Cancer, 2025, 13(1): e009544.
[38] EGAN CE, STEFANOVA D, AHMED A, et al.CSPG4 Is a Potential Therapeutic Target in Anaplastic Thyroid Cancer[J]. Thyroid, 2021, 31(10): 1481-1493.
[39] CATTANEO G, VENTIN M, ARYA S, et al.B7-H3 and CSPG4-Targeted CAR T Cells as Potent Effectors in Anaplastic Thyroid Cancer[J]. J Exp Clin Cancer Res, 2025, 44(1): 248.
[40] GIULIA C, MARCO V, VENKATA RAO V, et al.CSPG4-Targeted CAR T Cells Demonstrate Potent Antitumor Activity in an Orthotopic Murine Model of Anaplastic Thyroid Cancer[J]. J Immunother Cancer, 2023, 11(Suppl 1): A1-A1731.
[41] QIN AC, QIAN Y, MA YY, et al.Long Non-Coding RNA RP11-395G23.3 Acts as a Competing Endogenous RNA of miR-124-3p to Regulate ROR1 in Anaplastic Thyroid Carcinoma[J]. Front Genet, 2021, 12: 673242.
[42] CHERNYAKOV D, SKOROBOHATKO O, EDEMIR B, et al.ROR1-CAR T-Cells as Novel Treatment Strategy for Anaplastic Thyroid Carcinoma[J]. Journal for ImmunoTherapy of Cancer, 2022, 10: A22-A23.
[43] YOUNG RM, ENGEL NW, USLU U, et al.Next-Generation CAR T-Cell Therapies[J]. Cancer Discov, 2022, 12(7): 1625-1633.
[44] ALBELDA SM.CAR T Cell Therapy for Patients with Solid Tumours: Key Lessons to Learn and Unlearn[J]. Nat Rev Clin Oncol, 2024, 21(1): 47-66.
[45] HOU AJ, CHEN LC, CHEN YY.Navigating CAR-T Cells through the Solid-Tumour Microenvironment[J]. Nat Rev Drug Discov, 2021, 20(7): 531-550.
[46] LANDONI E, WOODCOCK MG, BARRAGAN G, et al.IL-12 Reprograms CAR-Expressing Natural Killer T Cells to Long-Lived Th1-Polarized Cells with Potent Antitumor Activity[J]. Nat Commun, 2024, 15(1): 89.
[47] LEE D, DUNN ZS, GUO W, et al.Unlocking the Potential of Allogeneic Vδ2 T Cells for Ovarian Cancer Therapy Through CD16 Biomarker Selection and CAR/IL-15 Engineering[J]. Nat Commun, 2023, 14(1): 6942.
[48] OUYANG W, O'GARRA A. IL-10 Family Cytokines IL-10 and IL-22: from Basic Science to Clinical Translation[J]. Immunity, 2019, 50(4): 871-891.
[49] REA A, SANTANA-HERNÁNDEZ S, VILLANUEVA J, et al. Enhancing Human NK Cell Antitumor Function by Knocking out SMAD4 to Counteract TGF-β and Activin A Suppression[J]. Nat Immunol, 2025, 26(4): 582-594.
[50] NIU C, WEI H, PAN X, et al. Foxp3 Confers Long-Term Efficacy of Chimeric Antigen Receptor-T Cells via Metabolic Reprogramming[J]. Cell Metab, 2025, 37(6): 1426-1441. e7.
[51] VINCENT RL, GURBATRI CR, LI F, et al.Probiotic-Guided CAR-T Cells for Solid Tumor Targeting[J]. Science, 2023, 382(6667): 211-218.
[52] KUAI R, OCHYL LJ, BAHJAT KS, et al.Designer Vaccine Nanodiscs for Personalized Cancer Immunotherapy[J]. Nat Mater, 2017, 16(4): 489-496.
[53] WANG Y, WANG Y, REN Y, et al.Metabolic Modulation of Immune Checkpoints and Novel Therapeutic Strategies in Cancer[J]. Semin Cancer Biol, 2022, 86(Pt 3): 542-565.
[54] CAO Q, WANG Y, CHEN J, et al.Targeting Inflammation with Chimeric Antigen Receptor Macrophages Using a Signal Switch[J]. Nat Biomed Eng, 2025, 9(9): 1502-1516.
[55] ZHOU X, ZHANG S, YANG W, et al. Restoring NK Cell Cytotoxicity Post-Cryopreservation via Synthetic Cells[J/OL]. Adv Sci (Weinh), (2025-09-18)[2025-10-19]. https://pubmed.ncbi.nlm.nih.gov/40966444/.
[56] LI YR, ZHU Y, LI Z, et al. Allogeneic Stem Cell-Engineered EGFRvIII-Specific CAR-NKT Cells for Treating Glioblastoma with Enhanced Efficacy and Safety[J/OL]. Molecular Therapy, (2025-09-12)[2025-10-19]. https://pubmed.ncbi.nlm.nih.gov/40946163/.