{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:25:52Z","timestamp":1787063152841,"version":"build-2736575974"},"reference-count":74,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T00:00:00Z","timestamp":1752624000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea (NRF), funded by the Korean government (MSIT)","award":["NRF-2022R1A2C2005057"],"award-info":[{"award-number":["NRF-2022R1A2C2005057"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Thyroid cancer, the most frequently occurring endocrine neoplasm, comprises a heterogeneous group of histological subtypes, spanning from the indolent papillary thyroid carcinoma (PTC) to the rapidly progressive and lethal anaplastic thyroid carcinoma (ATC). Although conventional therapies, such as surgery and radioactive iodine (RAI), are effective for differentiated thyroid cancers, treatment resistance and poor prognosis remain major challenges in advanced and undifferentiated forms. In current times, growing attention has been directed toward the potential of Natural Killer (NK) cells as a promising immunotherapeutic avenue. These innate immune cells are capable of direct cytotoxicity against tumor cells, but their efficiency is frequently compromised by the immunosuppressive tumor microenvironment (TME), which inhibits NK cell activation, infiltration, and persistence. This review explores the dynamic interaction between NK cells and the TME in thyroid cancer, detailing key mechanisms of immune evasion, including the impact of suppressive cytokines, altered chemokine landscapes, and inhibitory ligand expression. We further discuss latest advancements in NK cell-based immunotherapies, including strategies for ex vivo expansion, genetic modification, and combinatorial approaches with checkpoint inhibitors or cytokines. Additionally, emerging modalities, such as NK cell-derived extracellular vesicles, are addressed. By combining mechanistic insights with advancing therapeutic techniques, this review provides a comprehensive perspective on NK cell-based interventions and their future potential in improving outcomes for patients with thyroid cancer.<\/jats:p>","DOI":"10.3390\/cells14141087","type":"journal-article","created":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T10:46:05Z","timestamp":1752662765000},"page":"1087","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Natural Killer Cell and Extracellular Vesicle-Based Immunotherapy in Thyroid Cancer: Advances, Challenges, and Future Perspectives"],"prefix":"10.3390","volume":"14","author":[{"given":"Kruthika","family":"Prakash","sequence":"first","affiliation":[{"name":"Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu 603203, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6987-0854","authenticated-orcid":false,"given":"Ramya Lakshmi","family":"Rajendran","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea"},{"name":"Cardiovascular Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea"},{"name":"BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0097-2553","authenticated-orcid":false,"given":"Sanjana","family":"Dhayalan","sequence":"additional","affiliation":[{"name":"Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu 603203, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0658-4604","authenticated-orcid":false,"given":"Prakash","family":"Gangadaran","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea"},{"name":"Cardiovascular Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7700-3929","authenticated-orcid":false,"given":"Byeong-Cheol","family":"Ahn","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea"},{"name":"Cardiovascular Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea"},{"name":"BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea"},{"name":"Department of Nuclear Medicine, Kyungpook National University Hospital, Daegu 41944, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kandasamy Nagarajan","family":"Aruljothi","sequence":"additional","affiliation":[{"name":"Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu 603203, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1007\/s13193-021-01429-y","article-title":"Thyroid Cancer: Global Burden and Trends","volume":"13","author":"Shank","year":"2022","journal-title":"Indian. J. Surg. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Forma, A., K\u0142odnicka, K., Paj\u0105k, W., Flieger, J., Teresi\u0144ska, B., Januszewski, J., and Baj, J. (2025). Thyroid Cancer: Epidemiology, Classification, Risk Factors, Diagnostic and Prognostic Markers, and Current Treatment Strategies. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26115173"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6251","DOI":"10.7150\/thno.57689","article-title":"Molecular mechanisms of radioactive iodine refractoriness in differentiated thyroid cancer: Impaired sodium iodide symporter (NIS) expression owing to altered signaling pathway activity and intracellular localization of NIS","volume":"11","author":"Oh","year":"2021","journal-title":"Theranostics"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.clon.2017.02.009","article-title":"Targeted therapy in thyroid cancer: State of the art","volume":"29","author":"Valerio","year":"2017","journal-title":"Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Gangadaran, P., Rajendran, R.L., and Ahn, B.C. (2020). Application of in vivo imaging techniques for monitoring natural killer cell migration and tumor infiltration. Cancers, 12.","DOI":"10.3390\/cancers12051318"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Zhu, L., Li, X.J., Kalimuthu, S., Gangadaran, P., Lee, H.W., Oh, J.M., Baek, S.H., Jeong, S.Y., Lee, S.-W., and Lee, J. (2017). Natural killer cell (NK-92MI)-based therapy for pulmonary metastasis of anaplastic thyroid cancer in a nude mouse model. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.00816"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1126\/science.1198687","article-title":"Innate or adaptive immunity? The example of natural killer cells","volume":"331","author":"Vivier","year":"2011","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e3657","DOI":"10.1002\/jgm.3657","article-title":"Prognosis and therapy in thyroid cancer by gene signatures related to natural killer cells","volume":"26","author":"Jin","year":"2024","journal-title":"J. Gene Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.coi.2018.03.013","article-title":"Next generation natural killer cells for cancer immunotherapy: The promise of genetic engineering","volume":"51","author":"Daher","year":"2018","journal-title":"Curr. Opin. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"112251","DOI":"10.1016\/j.mce.2024.112251","article-title":"Development of TSHR-CAR NK-92 cells for Differentiated Thyroid Cancer","volume":"589","author":"Zhou","year":"2024","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/ni1582","article-title":"Functions of natural killer cells","volume":"9","author":"Vivier","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Wang, D.R., Dou, L.Y., Sui, L.H., Xue, Y., and Xu, S. (2024). Natural killer cells in cancer immunotherapy. MedComm, 5.","DOI":"10.1002\/mco2.626"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4884","DOI":"10.7150\/jca.44506","article-title":"Immune microenvironment of thyroid cancer","volume":"11","author":"Yin","year":"2020","journal-title":"J. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Park, A., Lee, Y., Kim, M.S., Kang, Y.J., Park, Y.-J., Jung, H., Kim, T.-D., Lee, H.G., Choi, I., and Yoon, S.R. (2018). Prostaglandin E2 secreted by thyroid cancer cells contributes to immune escape through the suppression of natural killer (NK) cell cytotoxicity and NK cell differentiation. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01859"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Patterson, C., Hazime, K.S., Zelenay, S., and Davis, D.M. (2024). Prostaglandin E2 impacts multiple stages of the natural killer cell antitumor immune response. Eur. J. Immunol., 54.","DOI":"10.1002\/eji.202350635"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"E832","DOI":"10.1210\/jc.2013-3351","article-title":"Indoleamine 2,3-Dioxygenase 1 (IDO1) is up-regulated in thyroid carcinoma and drives the development of an immunosuppressant tumor microenvironment","volume":"99","author":"Moretti","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zheng, X., Sun, R., and Wei, T. (2024). Immune microenvironment in papillary thyroid carcinoma: Roles of immune cells and checkpoints in disease progression and therapeutic implications. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1438235"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1038\/s41416-018-0296-2","article-title":"Combinations of BRAF inhibitor and anti-PD-1\/PD-L1 antibody improve survival and tumour immunity in an immunocompetent model of orthotopic murine anaplastic thyroid cancer","volume":"119","author":"Gunda","year":"2018","journal-title":"Br. J. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.jaut.2012.07.009","article-title":"Interleukin-6 induces the generation of IL-10-producing Tr1 cells and suppresses autoimmune tissue inflammation","volume":"40","author":"Jin","year":"2013","journal-title":"J. Autoimmun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12902-022-01113-4","article-title":"Expression of T-cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif domains (TIGIT) in anaplastic thyroid carcinoma","volume":"22","author":"Nakazawa","year":"2022","journal-title":"BMC Endocr. Disord."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"104912","DOI":"10.1016\/j.oraloncology.2020.104744","article-title":"The role of immune checkpoint inhibitors in anaplastic thyroid cancer (Case Series)","volume":"109","author":"Sukari","year":"2020","journal-title":"Oral. Oncol."},{"key":"ref_23","first-page":"89","article-title":"Expansion and activation of natural killer cells for cancer immunotherapy","volume":"29","author":"Cho","year":"2009","journal-title":"Korean J. Lab. Med."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Romee, R., Rosario, M., Berrien-Elliott, M.M., Wagner, J.A., Jewell, B.A., Schappe, T., Leong, J.W., Abdel-Latif, S., Schneider, S.E., and Willey, S. (2016). Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci. Transl. Med., 8.","DOI":"10.1126\/scitranslmed.aaf2341"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Gurney, M., Kundu, S., Pandey, S., and O\u2019Dwyer, M. (2022). Feeder Cells at the Interface of Natural Killer Cell Activation, Expansion and Gene Editing. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.802906"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1111\/bjh.14570","article-title":"Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma","volume":"177","author":"Shah","year":"2017","journal-title":"Br. J. Haematol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Thongsin, N., and Wattanapanitch, M. (2022). A three-dimensional immune-oncology model for studying in vitro primary human NK cell cytotoxic activity. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0264366"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Br\u00f6ker, K., Sinelnikov, E., Gustavus, D., Schumacher, U., P\u00f6rtner, R., Hoffmeister, H., L\u00fcth, S., and Dammermann, W. (2019). Mass production of highly active NK cells for cancer immunotherapy in a GMP conform perfusion bioreactor. Front. Bioeng. Biotechnol., 7.","DOI":"10.3389\/fbioe.2019.00194"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1186\/s13287-023-03461-x","article-title":"Enhancing cord blood stem cell-derived NK cell growth and differentiation through hyperosmosis","volume":"14","author":"Wen","year":"2023","journal-title":"Stem Cell Res. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1038\/s41423-024-01207-0","article-title":"CAR-T and CAR-NK as cellular cancer immunotherapy for solid tumors","volume":"21","author":"Peng","year":"2024","journal-title":"Cell Mol. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8594","DOI":"10.1158\/1078-0432.CCR-04-0690","article-title":"EGFR is overexpressed in anaplastic thyroid cancer, and gefitinib inhibits its growth","volume":"10","author":"Schiff","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Xie, G., Dong, H., Liang, Y., Ham, J.D., Rizwan, R., and Chen, J. (2020). CAR-NK cells: A promising cellular immunotherapy for cancer. eBioMedicine, 59.","DOI":"10.1016\/j.ebiom.2020.102975"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Shobab, L., Al-Souri, D., Mathews-Kim, L., McCoy, M., Kuenstner, W., Hubbard, G.K., Kumari, S., Chou, J., Lee, W., and Rosen, J. (2024). PD-L1 expression varies in thyroid cancer types and is associated with decreased progression-free survival in anaplastic thyroid cancer. Cancers, 16.","DOI":"10.3390\/cancers16213632"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Silvestre, R.N., Eitler, J., de Azevedo, J.T.C., Tirapelle, M.C., Fantacini, D.M.C., de Souza, L.E.B., Swiech, K., Covas, D.T., Calado, R.T., and Montero, P.O. (2023). Engineering NK-CAR.19 cells with IL-15\/IL-15R\u03b1 complex improves proliferation and anti-tumor effect in vivo. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1226518"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"de Rham, C., Ferrari-Lacraz, S., Jendly, S., Schneiter, G., Dayer, J.M., and Villard, J. (2007). IL-2, IL-15, and IL-21 modulate the repertoire of mature human NK cell receptors. Arthritis Res. Ther., 9.","DOI":"10.1186\/ar2336"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Fuziwara, C.S., de Mello, D.C., and Kimura, E.T. (2022). Gene editing with CRISPR\/Cas and thyroid cancer: Where are we?. Cancers, 14.","DOI":"10.3390\/cancers14030844"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1158\/2326-6066.CIR-24-0384","article-title":"Fc\u03b3RIIIA (CD16) L48-H\/R polymorphism enhances NK cell-mediated ADCC via serial killing","volume":"13","author":"Maskalenko","year":"2025","journal-title":"Cancer Immunol. Res."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Boissel, L., Klingemann, H., Campbell, K., Nichols, K., Toneguzzo, F., Marcus, P., Williams, B., Keating, A., and Soon-Shiong, P. (2016). Abstract 2302: An \u2018off the shelf,\u2019 GMP-grade, IL-2-independent NK cell line expressing the high-affinity Fc-receptor to augment antibody therapeutics. Cancer Res., 76.","DOI":"10.1158\/1538-7445.AM2016-2302"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Gil, M.S.R., Pozas, J., Molina-Cerrillo, J., G\u00f3mez, J., Pian, H., Pozas, M., Carrato, A., Grande, E., and Alonso-Gordoa, T. (2020). Current and future role of tyrosine kinases inhibition in thyroid cancer: From biology to therapy. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21144951"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Suzuki, K., Iwai, H., Utsunomiya, K., Kono, Y., Kobayashi, Y., Van Bui, D., Sawada, S., Yun, Y., Mitani, A., and Kondo, N. (2021). Combination therapy with lenvatinib and radiation significantly inhibits thyroid cancer growth by uptake of tyrosine kinase inhibitor. Exp. Cell Res., 398.","DOI":"10.1016\/j.yexcr.2020.112390"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Crespo-Rodriguez, E., Bergerhoff, K., Bozhanova, G., Foo, S., Patin, E.C., Whittock, H., Buus, R., Haider, S., Muirhead, G., and Thway, K. (2020). Combining BRAF inhibition with oncolytic herpes simplex virus enhances the immune-mediated antitumor therapy of BRAF-mutant thyroid cancer. J. Immunother. Cancer, 8.","DOI":"10.1136\/jitc-2020-000698"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1007\/s00262-019-02372-2","article-title":"An IL-15-based superagonist ALT-803 enhances the NK cell response to cetuximab-treated squamous cell carcinoma of the head and neck","volume":"68","author":"Pinette","year":"2019","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1158\/1535-7163.MCT-19-1095","article-title":"Inhibition of Tumor Cell Growth and Cancer Stem Cell Expansion by a Bispecific Antibody Targeting EGFR and HER3","volume":"19","author":"Rau","year":"2020","journal-title":"Mol. Cancer Ther."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Gallardo-Zapata, J., P\u00e9rez-Figueroa, E., Olivar-L\u00f3pez, V., Medina-Sans\u00f3n, A., Jim\u00e9nez-Hern\u00e1ndez, E., Ortega, E., and Maldonado-Bernal, C. (2024). TLR Agonists Modify NK Cell Activation and Increase Its Cytotoxicity in Acute Lymphoblastic Leukemia. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202404.1527.v1"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2523","DOI":"10.1007\/s12253-020-00834-y","article-title":"HDAC inhibition induces PD-L1 expression in a novel anaplastic thyroid cancer cell line","volume":"26","author":"Rittler","year":"2020","journal-title":"Pathol. Oncol. Res."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Seel, K., Schirrmann, R.L., Stowitschek, D., Ioseliani, T., Roiter, L., Knierim, A., and Andr\u00e9, M.C. (2024). Blockade of the TIGIT-CD155\/CD112 axis enhances functionality of NK-92 but not cytokine-induced memory-like NK cells toward CD155-expressing acute myeloid leukemia. Cancer Immunol. Immunother., 73.","DOI":"10.1007\/s00262-024-03766-7"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Hu, J., Liu, K., Ghosh, C., Khaket, T.P., Shih, H., and Kebebew, E. (2024). Anaplastic thyroid cancer spheroids as preclinical models to test therapeutics. J. Exp. Clin. Cancer Res., 43.","DOI":"10.1186\/s13046-024-03009-8"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1038\/s41590-018-0132-0","article-title":"Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity","volume":"19","author":"Zhang","year":"2018","journal-title":"Nat. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Liu, T., Fan, L., Huang, W., Chen, P., Liu, Y., Wang, S., Guo, K., Cheng, Y., and Han, Y. (2025). Harnessing NKG2D CAR-T cells with radiotherapy: A novel approach for esophageal squamous cell carcinoma treatment. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1589379"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5733","DOI":"10.1158\/1078-0432.CCR-14-0291","article-title":"Human anaplastic thyroid carcinoma cells are sensitive to NK cell-mediated lysis via ULBP2\/5\/6 and chemoattract NK cells","volume":"20","author":"Wennerberg","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1038\/icb.2013.111","article-title":"Advances in NKG2D ligand recognition and responses by NK cells","volume":"92","author":"Gasser","year":"2014","journal-title":"Immunol. Cell Biol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Tahara, M., Kiyota, N., Yamazaki, T., Chayahara, N., Nakano, K., Inagaki, L., Toda, K., Enokida, T., Minami, H., and Imamura, Y. (2017). Lenvatinib for anaplastic thyroid cancer. Front. Oncol., 7.","DOI":"10.3389\/fonc.2017.00025"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1038\/jid.2012.376","article-title":"The immunocytokine L19-IL2 eradicates cancer when used in combination with CTLA-4 blockade or with L19-TNF","volume":"133","author":"Schwager","year":"2013","journal-title":"J. Invest. Dermatol."},{"key":"ref_54","first-page":"1820","article-title":"Local delivery of cell surface-targeted immunocytokines programs systemic anti-tumor immunity","volume":"25","author":"Santollani","year":"2024","journal-title":"bioRxiv"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1158\/2326-6066.CIR-23-0151","article-title":"Sequential exposure to IL21 and IL15 during human natural killer cell expansion optimizes yield and function","volume":"11","author":"Zhang","year":"2023","journal-title":"Cancer Immunol. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1056\/NEJMoa1910607","article-title":"Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors","volume":"382","author":"Liu","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"113","DOI":"10.2217\/pgs-2023-0234","article-title":"Targeting RET mutation in medullary thyroid cancer","volume":"25","author":"Assi","year":"2024","journal-title":"Pharmacogenomics"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Zhao, X., Cai, L., Hu, Y., and Wang, H. (2020). Cord-blood natural killer cell-based immunotherapy for cancer. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.584099"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Wang, L., Wang, Y., He, X., Mo, Z., Zhao, M., Liang, X., Hu, K., Wang, K., Yue, Y., and Mo, G. (2025). CD70-targeted iPSC-derived CAR-NK cells display potent function against tumors and alloreactive T cells. Cell Rep. Med., 6.","DOI":"10.1016\/j.xcrm.2024.101889"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.biomaterials.2018.10.034","article-title":"Enhancement of antitumor potency of extracellular vesicles derived from natural killer cells by IL-15 priming","volume":"190\u2013191","author":"Zhu","year":"2019","journal-title":"Biomaterials"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Morcillo-Mart\u00edn-Romo, P., Valverde-Pozo, J., Ortiz-Bueno, M., Arnone, M., Espinar-Barranco, L., Espinar-Barranco, C., and Garc\u00eda-Rubi\u00f1o, M.E. (2025). Role of NK cells in cancer immunotherapy: Mechanisms and therapeutic advances. Biomedicines, 13.","DOI":"10.3390\/biomedicines13040857"},{"key":"ref_62","first-page":"1382","article-title":"Lenvatinib promotes antitumor immunity by enhancing the tumor infiltration and activation of NK cells","volume":"9","author":"Zhang","year":"2019","journal-title":"Am. J. Cancer Res."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Wu, F., Xie, M., Hun, M., She, Z., Li, C., Luo, S., Chen, X., Wan, W., Wen, C., and Tian, J. (2021). Natural Killer Cell-Derived Extracellular Vesicles: Novel Players in Cancer Immunotherapy. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.658698"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"358","DOI":"10.15407\/exp-oncology.2024.04.358","article-title":"Natural Killer Cell-Derived Exosome Mimetics as Natural Nanocarriers for In Vitro Delivery of Chemotherapeutics to Thyroid Cancer Cells","volume":"46","author":"Zhu","year":"2024","journal-title":"Exp. Oncol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2833","DOI":"10.4049\/jimmunol.1101988","article-title":"Immune surveillance properties of human NK cell-derived exosomes","volume":"189","author":"Lugini","year":"2012","journal-title":"J. Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1089\/104303403322611755","article-title":"Gene therapy of anaplastic thyroid carcinoma with a single-chain IL-12 fusion protein","volume":"14","author":"Shi","year":"2003","journal-title":"Hum. Gene Ther."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Meng, F., Zhang, S., Xie, J., Zhou, Y., Wu, Q., Lu, B., Zhou, S., Zhao, X., and Li, Y. (2023). Leveraging CD16 fusion receptors to remodel the immune response for enhancing anti-tumor immunotherapy in iPSC-derived NK cells. J. Hematol. Oncol., 16.","DOI":"10.1186\/s13045-023-01455-z"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"P\u00f6rtner, R., Sebald, C., Parida, S.K., and Hoffmeister, H. (2019). Single-use bioreactors for immune cell therapeutic manufacturing. Single-Use Technology in Biopharmaceutical Manufacture, Wiley.","DOI":"10.1002\/9781119477891.ch30"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Li, S., Han, H., Yang, K., Li, X., Ma, L., Yang, Z., and Zhao, Y.-X. (2025). Emerging role of metabolic reprogramming in the immune microenvironment and immunotherapy of thyroid cancer. Int. Immunopharmacol., 144.","DOI":"10.1016\/j.intimp.2024.113702"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1002\/ijc.33859","article-title":"NKG2A is a late immune checkpoint on CD8 T cells and marks repeated stimulation and cell division","volume":"150","author":"Borst","year":"2022","journal-title":"Int. J. Cancer"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Peng, H., Li, L., Zuo, C., Chen, M.Y., Zhang, X., Myers, N.B., Hogg, G.D., DeNardo, D.G., Goedegebuure, S.P., and Hawkins, W.G. (2022). Combination TIGIT\/PD-1 blockade enhances the efficacy of neoantigen vaccines in a model of pancreatic cancer. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1039226"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/s41577-020-0306-5","article-title":"A guide to cancer immunotherapy: From T cell basic science to clinical practice","volume":"20","author":"Waldman","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.stem.2018.07.007","article-title":"Off-the-shelf CAR-NK cells for cancer immunotherapy","volume":"23","author":"Siegler","year":"2018","journal-title":"Cell Stem Cell"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Zhao, T., You, J., Wang, C., Li, B., Liu, Y., Shao, M., Zhao, W., and Zhou, C. (2025). Cell-based immunotherapies for solid tumors: Advances and future directions. Front. 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