{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T04:52:16Z","timestamp":1794027136155,"version":"4.8.0"},"reference-count":195,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"state assignment of the Federal State Budgetary Scientific Institution \u201cResearch Centre for Medical Genetics\u201d of the Ministry of Science and Higher Education of the Russian Federation","award":["124052700009-2"],"award-info":[{"award-number":["124052700009-2"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>CAR-T cell therapy is a promising method of cancer treatment, but it has some disadvantages. These disadvantages have led scientists to explore the use of safer CAR-NK cells and new genetic modifications in order to improve the effectiveness of CAR cells. In this paper, we analyze existing approaches to modifying CAR-NK cells and discuss the results of clinical trials involving CAR-NK therapies. Conventionally, approaches to NK cell modification can be divided into three main groups: strategies to enhance antitumor cytotoxicity, strategies to improve the survival of CAR-NK cells and prolong their persistence in the body, and strategies to increase the safety of CAR-NK cells. The effects of CAR-NK cells on different tumor types are presented, and the number of clinical trials involving CAR-NK cells has been increasing every year, with positive results so far. As of September 2025, all the trials are in the early 1\u20132 stages of research, and it is expected that the first CAR-NK product will be approved in the near future.<\/jats:p>","DOI":"10.3390\/cells14231858","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T15:29:47Z","timestamp":1764084587000},"page":"1858","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Strategies for the Development of NK Cell-Based Therapies for Cancer Treatment"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3761-3993","authenticated-orcid":false,"given":"Tatiana","family":"Budagova","sequence":"first","affiliation":[{"name":"Federal State Budgetary Scientific Institution Research Centre for Medical Genetics, Moskvorechye Str. 1, Moscow 115522, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5035-6396","authenticated-orcid":false,"given":"Anna","family":"Efremova","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Scientific Institution Research Centre for Medical Genetics, Moskvorechye Str. 1, Moscow 115522, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8048-0769","authenticated-orcid":false,"given":"Margarita","family":"Maiak","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Scientific Institution Research Centre for Medical Genetics, Moskvorechye Str. 1, Moscow 115522, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2438-1605","authenticated-orcid":false,"given":"Dmitry","family":"Goldshtein","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Scientific Institution Research Centre for Medical Genetics, Moskvorechye Str. 1, Moscow 115522, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"51","DOI":"10.14216\/kjco.24009","article-title":"The Evolution of Cancer Immunotherapy: A Comprehensive Review of Its History and Current Perspectives","volume":"20","author":"Ahuja","year":"2024","journal-title":"Korean J. Clin. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Mitra, A., Kumar, A., Amdare, N.P., and Pathak, R. (2024). Current Landscape of Cancer Immunotherapy: Harnessing the Immune Arsenal to Overcome Immune Evasion. Biology, 13.","DOI":"10.3390\/biology13050307"},{"key":"ref_3","unstructured":"Center for Biologics Evaluation and Research (2025). Approved Cellular and Gene Therapy Products."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s10529-023-03461-0","article-title":"Recent Advances and Current Challenges in CAR-T Cell Therapy","volume":"46","author":"Joy","year":"2024","journal-title":"Biotechnol. Lett."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1007\/s12032-023-02146-y","article-title":"Revolutionizing Cancer Treatment: A Comprehensive Review of CAR-T Cell Therapy","volume":"40","author":"Dabas","year":"2023","journal-title":"Med. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/s41408-021-00459-7","article-title":"CAR-T Cell Therapy: Current Limitations and Potential Strategies","volume":"11","author":"Sterner","year":"2021","journal-title":"Blood Cancer J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1053\/j.seminhematol.2024.08.003","article-title":"Mobilizing CARs: Benefits, Drawbacks, and Directions for Outpatient CAR T-Cell Therapy","volume":"61","author":"Woo","year":"2024","journal-title":"Semin. Hematol."},{"key":"ref_8","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_9","doi-asserted-by":"crossref","unstructured":"Li, W., Wang, X., Zhang, X., Aziz, A.U.R., and Wang, D. (2024). CAR-NK Cell Therapy: A Transformative Approach to Overcoming Oncological Challenges. Biomolecules, 14.","DOI":"10.20944\/preprints202406.1007.v1"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Balkhi, S., Zuccolotto, G., Di Spirito, A., Rosato, A., and Mortara, L. (2025). CAR-NK Cell Therapy: Promise and Challenges in Solid Tumors. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1574742"},{"key":"ref_11","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_12","doi-asserted-by":"crossref","first-page":"6543","DOI":"10.1182\/blood-2024-198684","article-title":"Safety and Efficacy of FT522, a First-in-Class, Multi-Antigen Targeted, Off-the-Shelf, iPSC-Derived CD19 CAR NK Cell Therapy with Alloimmune Defense Receptor (ADR) in Relapsed\/Refractory B-Cell Lymphoma","volume":"144","author":"Bachanova","year":"2024","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Jiang, P., Jing, S., Sheng, G., and Jia, F. (2024). The Basic Biology of NK Cells and Its Application in Tumor Immunotherapy. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1420205"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1038\/s41586-023-06945-1","article-title":"Natural Killer Cell Therapies","volume":"626","author":"Vivier","year":"2024","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1007\/s10555-025-10242-w","article-title":"The Diversity of Natural Killer Cell Functional and Phenotypic States in Cancer","volume":"44","author":"Rishabh","year":"2025","journal-title":"Cancer Metastasis Rev."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Khanal, S., and Bhattarai, N. (2025). A Scalable Protocol for Ex Vivo Production of CAR-Engineered Human NK Cells. Methods Protoc., 8.","DOI":"10.3390\/mps8050102"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1186\/s40164-024-00578-4","article-title":"Natural Killer Cell Biology and Therapy in Multiple Myeloma: Challenges and Opportunities","volume":"13","author":"Bisht","year":"2024","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4684268","DOI":"10.1155\/2016\/4684268","article-title":"NK Cells, Tumor Cell Transition, and Tumor Progression in Solid Malignancies: New Hints for NK-Based Immunotherapy?","volume":"2016","author":"Cantoni","year":"2016","journal-title":"J. Immunol. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1158\/2326-6066.CIR-21-1075","article-title":"Targeting Macrophages with CAR T Cells Delays Solid Tumor Progression and Enhances Antitumor Immunity","volume":"10","author":"Mollaoglu","year":"2022","journal-title":"Cancer Immunol. Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Kim, S.K., and Cho, S.W. (2022). The Evasion Mechanisms of Cancer Immunity and Drug Intervention in the Tumor Microenvironment. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.868695"},{"key":"ref_21","first-page":"4060","article-title":"The Bcl-2 Transgene Protects T Cells from Renal Cell Carcinoma-Mediated Apoptosis1","volume":"9","author":"Molto","year":"2003","journal-title":"Clin. Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.1182\/blood.V95.6.2015","article-title":"Tumor-Induced Apoptosis of T Lymphocytes: Elucidation of Intracellular Apoptotic Events","volume":"95","author":"Gastman","year":"2000","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Bashiri Dezfouli, A., Yazdi, M., Pockley, A.G., Khosravi, M., Kobold, S., Wagner, E., and Multhoff, G. (2021). NK Cells Armed with Chimeric Antigen Receptors (CAR): Roadblocks to Successful Development. Cells, 10.","DOI":"10.3390\/cells10123390"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s12967-019-02206-w","article-title":"IL-23 and PSMA-Targeted Duo-CAR T Cells in Prostate Cancer Eradication in a Preclinical Model","volume":"18","author":"Wang","year":"2020","journal-title":"J. Transl. Med."},{"key":"ref_25","unstructured":"Kulemzin, S., Kuznetsova, V., Mamonkin, M., Taranin, A., and Gorchakov, A. (2025, September 28). Engineering Chimeric Antigen Receptors. Available online: https:\/\/cyberleninka.ru\/article\/n\/osnovy-dizayna-himernyh-antigennyh-retseptorov\/viewer."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Yang, K., Zhao, Y., Sun, G., Zhang, X., Cao, J., Shao, M., Liang, X., and Wang, L. (2023). Clinical Application and Prospect of Immune Checkpoint Inhibitors for CAR-NK Cell in Tumor Immunotherapy. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1081546"},{"key":"ref_27","unstructured":"(2025, October 12). The Human Protein Atlas. Available online: https:\/\/www.proteinatlas.org\/."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"137","DOI":"10.3892\/or.2024.8796","article-title":"A Potential Mechanism of Tumor Immune Escape: Regulation and Application of Soluble Natural Killer Group 2 Member D Ligands (Review)","volume":"52","author":"Huang","year":"2024","journal-title":"Oncol. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Tan, G., Spillane, K.M., and Maher, J. (2023). The Role and Regulation of the NKG2D\/NKG2D Ligand System in Cancer. Biology, 12.","DOI":"10.3390\/biology12081079"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1186\/s13045-021-01083-5","article-title":"Chimeric Antigen Receptor Natural Killer (CAR-NK) Cell Design and Engineering for Cancer Therapy","volume":"14","author":"Gong","year":"2021","journal-title":"J. Hematol. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1093\/protein\/6.8.989","article-title":"An Improved Linker for Single-Chain Fv with Reduced Aggregation and Enhanced Proteolytic Stability","volume":"6","author":"Whitlow","year":"1993","journal-title":"Protein Eng."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1186\/s40164-024-00583-7","article-title":"The Development and Application of Chimeric Antigen Receptor Natural Killer (CAR-NK) Cells for Cancer Therapy: Current State, Challenges and Emerging Therapeutic Advances","volume":"13","author":"Yao","year":"2024","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/s41419-024-06438-7","article-title":"Chimeric Antigen Receptor-Based Natural Killer Cell Immunotherapy in Cancer: From Bench to Bedside","volume":"15","author":"Zhang","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.omto.2018.10.006","article-title":"Preclinical Development of Bivalent Chimeric Antigen Receptors Targeting Both CD19 and CD22","volume":"11","author":"Qin","year":"2018","journal-title":"Mol. Ther. Oncolytics"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Park, E., Mun, H., Seo, E., Hwang, S., Lee, J.H., Song, S., Sung, H., Kim, H.-Y., and Kwon, M.-J. (2024). CAR NK92 Cells Targeting BCMA Can Effectively Kill Multiple Myeloma Cells Both In Vitro and In Vivo. Biomedicines, 12.","DOI":"10.3390\/biomedicines12010248"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4121","DOI":"10.1038\/s41467-022-31810-6","article-title":"The Surfaceome of Multiple Myeloma Cells Suggests Potential Immunotherapeutic Strategies and Protein Markers of Drug Resistance","volume":"13","author":"Ferguson","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Bernard, G., and Evgin, L. (2025). Non-Signaling but All Important: How the Linker, Hinge, and Transmembrane Domains in the CAR Hold It All Together. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1664403"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/s41392-021-00823-w","article-title":"T Cell Receptor (TCR) Signaling in Health and Disease","volume":"6","author":"Shah","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/s13045-019-0732-7","article-title":"2B4 Costimulatory Domain Enhancing Cytotoxic Ability of Anti-CD5 Chimeric Antigen Receptor Engineered Natural Killer Cells against T Cell Malignancies","volume":"12","author":"Xu","year":"2019","journal-title":"J. Hematol. Oncol."},{"key":"ref_40","first-page":"36","article-title":"Cluster of Differentiation 19 Chimeric Antigen Receptor T-Cell Therapy in Pediatric Acute Lymphoblastic Leukemia","volume":"20","author":"Fu","year":"2020","journal-title":"Oncol. Lett."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Miao, L., Zhang, J., Huang, B., Zhang, Z., Wang, S., Tang, F., Teng, M., and Li, Y. (2022). Special Chimeric Antigen Receptor (CAR) Modifications of T Cells: A Review. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.832765"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Ku, K.S., Tang, J., Chen, Y., and Shi, Y. (2024). Current Advancements in Anti-Cancer Chimeric Antigen Receptor T Cell Immunotherapy and How Nanotechnology May Change the Game. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25105361"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3247","DOI":"10.2147\/CMAR.S253565","article-title":"DNAM1 and 2B4 Costimulatory Domains Enhance the Cytotoxicity of Anti-GPC3 Chimeric Antigen Receptor-Modified Natural Killer Cells Against Hepatocellular Cancer Cells In Vitro","volume":"12","author":"Huang","year":"2020","journal-title":"Cancer Manag. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/s13046-025-03351-5","article-title":"A Chimeric Antigen Receptor Tailored to Integrate Complementary Activation Signals Potentiates the Antitumor Activity of NK Cells","volume":"44","author":"Yi","year":"2025","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Zhi, L., Zhang, Z., Gao, Q., Shang, C., He, W., Wang, Y., Guo, C., Niu, Z., and Zhu, W. (2025). CAR-NK Cells with Dual Targeting of PD-L1 and MICA\/B in Lung Cancer Tumor Models. BMC Cancer, 25.","DOI":"10.1186\/s12885-025-13821-w"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6122","DOI":"10.1158\/1538-7445.AM2025-6122","article-title":"Abstract 6122: Off-the-Shelf BCMA\/GPRC5D Dual Targeted CAR-NK Cell Therapy Combined with Daratumumab in Treating Multiple Myeloma","volume":"85","author":"Wang","year":"2025","journal-title":"Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4225","DOI":"10.1016\/j.cell.2025.05.038","article-title":"An iPSC-Derived CD19\/BCMA CAR-NK Therapy in a Patient with Systemic Sclerosis","volume":"188","author":"Wang","year":"2025","journal-title":"Cell"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1080\/07357907.2021.2005798","article-title":"Engineering Novel CD19\/CD22 Dual-Target CAR-T Cells for Improved Anti-Tumor Activity","volume":"40","author":"Zeng","year":"2022","journal-title":"Cancer Investig."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1038\/s41591-022-02003-x","article-title":"KIR-Based Inhibitory CARs Overcome CAR-NK Cell Trogocytosis-Mediated Fratricide and Tumor Escape","volume":"28","author":"Li","year":"2022","journal-title":"Nat. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1186\/s13045-023-01455-z","article-title":"Leveraging CD16 Fusion Receptors to Remodel the Immune Response for Enhancing Anti-Tumor Immunotherapy in iPSC-Derived NK Cells","volume":"16","author":"Meng","year":"2023","journal-title":"J. Hematol. Oncol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1038\/s41392-024-02005-w","article-title":"Comprehensive Snapshots of Natural Killer Cells Functions, Signaling, Molecular Mechanisms and Clinical Utilization","volume":"9","author":"Chen","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1002\/JLB.2MR1218-501R","article-title":"Role of ADAM17 as a Regulatory Checkpoint of CD16A in NK Cells and as a Potential Target for Cancer Immunotherapy","volume":"105","author":"Wu","year":"2019","journal-title":"J. Leukoc. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Kim, J., Lee, J.Y., Kim, H.G., Kwak, M.W., and Kang, T.H. (2021). Fc Receptor Variants and Disease: A Crucial Factor to Consider in the Antibody Therapeutics in Clinic. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22179489"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1038\/s41586-024-07864-5","article-title":"Structural Insights into the High-Affinity IgE Receptor Fc\u03b5RI Complex","volume":"633","author":"Deng","year":"2024","journal-title":"Nature"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1111\/j.1600-065X.2006.00457.x","article-title":"Activation, Coactivation, and Costimulation of Resting Human Natural Killer Cells","volume":"214","author":"Bryceson","year":"2006","journal-title":"Immunol. Rev."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.1038\/s41590-023-01663-2","article-title":"CD3\u03b6 ITAMs Enable Ligand Discrimination and Antagonism by Inhibiting TCR Signaling in Response to Low-Affinity Peptides","volume":"24","author":"Gaud","year":"2023","journal-title":"Nat. Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e20220022","DOI":"10.1084\/jem.20220022","article-title":"The CD3\u03b6 Adaptor Structure Determines Functional Differences Between Human and Mouse CD16 Fc Receptor Signaling","volume":"219","author":"Aguilar","year":"2022","journal-title":"J. Exp. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1182\/blood.2019000621","article-title":"Pluripotent Stem Cell-Derived NK Cells with High-Affinity Noncleavable CD16a Mediate Improved Antitumor Activity","volume":"135","author":"Zhu","year":"2020","journal-title":"Blood"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Mahaweni, N.M., Olieslagers, T.I., Rivas, I.O., Molenbroeck, S.J.J., Groeneweg, M., Bos, G.M.J., Tilanus, M.G.J., Voorter, C.E.M., and Wieten, L. (2018). A Comprehensive Overview of FCGR3A Gene Variability by Full-Length Gene Sequencing Including the Identification of V158F Polymorphism. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-34258-1"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"4220","DOI":"10.1182\/blood.V94.12.4220","article-title":"Variant Genotypes of the Low-Affinity Fc\u03b3 Receptors in Two Control Populations and a Review of Low-Affinity Fc\u03b3 Receptor Polymorphisms in Control and Disease Populations","volume":"94","author":"Lehrnbecher","year":"1999","journal-title":"Blood"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2531","DOI":"10.1002\/ijc.32618","article-title":"CD16-158-Valine Chimeric Receptor T Cells Overcome the Resistance of KRAS-Mutated Colorectal Carcinoma Cells to Cetuximab","volume":"146","author":"Arriga","year":"2020","journal-title":"Int. J. Cancer"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.jcyt.2023.11.009","article-title":"Engineering of CD34+ Progenitor-Derived Natural Killer Cells with Higher-Affinity CD16a for Enhanced Antibody-Dependent Cellular Cytotoxicity","volume":"26","author":"Hooijmaijers","year":"2024","journal-title":"Cytotherapy"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/s41416-018-0341-1","article-title":"High-Affinity CD16-Polymorphism and Fc-Engineered Antibodies Enable Activity of CD16-Chimeric Antigen Receptor-Modified T Cells for Cancer Therapy","volume":"120","author":"Rataj","year":"2019","journal-title":"Br. J. Cancer"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Patel, K.R., Rodriguez Benavente, M.C., Lorenz, W.W., Mace, E.M., and Barb, A.W. (2021). Fc \u03b3 Receptor IIIa\/CD16a Processing Correlates with the Expression of Glycan-Related Genes in Human Natural Killer Cells. J. Biol. Chem., 296.","DOI":"10.1074\/jbc.RA120.015516"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Jing, Y., Ni, Z., Wu, J., Higgins, L., Markowski, T.W., Kaufman, D.S., and Walcheck, B. (2015). Identification of an ADAM17 Cleavage Region in Human CD16 (Fc\u03b3RIII) and the Engineering of a Non-Cleavable Version of the Receptor in NK Cells. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0121788"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Daly, J., Carlsten, M., and O\u2019Dwyer, M. (2019). Sugar Free: Novel Immunotherapeutic Approaches Targeting Siglecs and Sialic Acids to Enhance Natural Killer Cell Cytotoxicity Against Cancer. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01047"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1038\/s41587-025-02629-5","article-title":"Engineering Innate Immune Cells for Cancer Immunotherapy","volume":"43","author":"Tarannum","year":"2025","journal-title":"Nat. Biotechnol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1007\/s00262-022-03275-5","article-title":"TCR Extracellular Domain Genetically Linked to CD28, 2B4\/41BB and DAP10\/CD3\u03b6 -Engineered NK Cells Mediates Antitumor Effects","volume":"72","author":"Li","year":"2023","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Capuano, C., Pighi, C., Battella, S., Pulcinelli, F., Santoro, C., Ferretti, A., Turriziani, O., De Federicis, D., Fionda, C., and Scium\u00e8, G. (2022). (Auto)Antibody Responses Shape Memory NK Cell Pool Size and Composition. Biomedicines, 10.","DOI":"10.3390\/biomedicines10030625"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.cytogfr.2017.08.002","article-title":"Immunobiology of the IL-15\/IL-15R\u03b1 Complex as an Antitumor and Antiviral Agent","volume":"38","author":"Guo","year":"2017","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Budagova, T., Efremova, A., Usman, N., Mokrousova, D., and Goldshtein, D. (2025). Differentiating Induced Pluripotent Stem Cells into Natural Killer Cells for Adoptive Cell Immunotherapies\u2014Comparative Characterization of Current Protocols. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26031107"},{"key":"ref_72","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 the IL-15\/IL-15R\u03b1 Complex Improved Proliferation and Anti-Tumor Effect In Vivo. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1226518"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1074\/jbc.M508624200","article-title":"Soluble Interleukin-15 Receptor Alpha (IL-15R Alpha)-Sushi as a Selective and Potent Agonist of IL-15 Action through IL-15R Beta\/Gamma. Hyperagonist IL-15 x IL-15R Alpha Fusion Proteins","volume":"281","author":"Mortier","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s12931-020-1301-x","article-title":"The IL-15\/sIL-15R\u03b1 Complex Modulates Immunity Without Effect on Asthma Features in Mouse","volume":"21","author":"Moui","year":"2020","journal-title":"Respir. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"kyae002","DOI":"10.1093\/discim\/kyae002","article-title":"Signalling Mechanisms Driving Homeostatic and Inflammatory Effects of Interleukin-15 on Tissue Lymphocytes","volume":"3","author":"Skariah","year":"2024","journal-title":"Discov. Immunol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1016\/j.celrep.2013.08.021","article-title":"IL-15 Cis Presentation Is Required for Optimal NK Cell Activation in Lipopolysaccharide-Mediated Inflammatory Conditions","volume":"4","author":"Zanoni","year":"2013","journal-title":"Cell Rep."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1038\/ni1492","article-title":"Crystal Structure of the IL-15-IL-15Ralpha Complex, a Cytokine-Receptor Unit Presented in Trans","volume":"8","author":"Chirifu","year":"2007","journal-title":"Nat. Immunol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/nri3919","article-title":"IL-15 Functions as a Danger Signal to Regulate Tissue-Resident T Cells and Tissue Destruction","volume":"15","author":"Jabri","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/s41420-024-01815-9","article-title":"Breakthrough of Solid Tumor Treatment: CAR-NK Immunotherapy","volume":"10","author":"Wang","year":"2024","journal-title":"Cell Death Discov."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/j.scib.2025.01.002","article-title":"CAR-NK Cell Therapy: A Potential Antiviral Platform","volume":"70","author":"Lin","year":"2025","journal-title":"Sci. Bull."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"6642","DOI":"10.1074\/jbc.M513118200","article-title":"The Structure of the Interleukin-15 Alpha Receptor and Its Implications for Ligand Binding","volume":"281","author":"Lorenzen","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"29862","DOI":"10.1074\/jbc.270.50.29862","article-title":"Functional Characterization of the Human Interleukin-15 Receptor Alpha Chain and Close Linkage of IL15RA and IL2RA Genes","volume":"270","author":"Anderson","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"E7788","DOI":"10.1073\/pnas.1610544113","article-title":"Tethered IL-15 Augments Antitumor Activity and Promotes a Stem-Cell Memory Subset in Tumor-Specific T Cells","volume":"113","author":"Hurton","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1186\/s12967-024-04982-6","article-title":"Combined Therapy of CAR-IL-15\/IL-15R\u03b1-T Cells and GLIPR1 Knockdown in Cancer Cells Enhanced Anti-Tumor Effect against Gastric Cancer","volume":"22","author":"Ye","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"8439","DOI":"10.1038\/s41467-024-52388-1","article-title":"CRISPR\/Cas9 Editing of NKG2A Improves the Efficacy of Primary CD33-Directed Chimeric Antigen Receptor Natural Killer Cells","volume":"15","author":"Bexte","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.1056\/NEJMoa2409029","article-title":"Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma","volume":"392","author":"Dimopoulos","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s13045-016-0283-0","article-title":"Daratumumab: A First-in-Class CD38 Monoclonal Antibody for the Treatment of Multiple Myeloma","volume":"9","author":"Sanchez","year":"2016","journal-title":"J. Hematol. Oncol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e003804","DOI":"10.1136\/jitc-2021-003804","article-title":"High-Affinity CD16 Integration into a CRISPR\/Cas9-Edited CD38 Locus Augments CD38-Directed Antitumor Activity of Primary Human Natural Killer Cells","volume":"10","author":"Clara","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nature10491","article-title":"An Endogenous Tumour-Promoting Ligand of the Human Aryl Hydrocarbon Receptor","volume":"478","author":"Opitz","year":"2011","journal-title":"Nature"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"4605","DOI":"10.1182\/bloodadvances.2021004533","article-title":"Defining the AHR-Regulated Transcriptome in NK Cells Reveals Gene Expression Programs Relevant to Development and Function","volume":"5","author":"Trikha","year":"2021","journal-title":"Blood Adv."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"e009560","DOI":"10.1136\/jitc-2024-009560","article-title":"Precision Enhancement of CAR-NK Cells through Non-Viral Engineering and Highly Multiplexed Base Editing","volume":"13","author":"Wang","year":"2025","journal-title":"J. Immunother. Cancer"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e004244","DOI":"10.1136\/jitc-2021-004244","article-title":"Targeting CISH Enhances Natural Cytotoxicity Receptor Signaling and Reduces NK Cell Exhaustion to Improve Solid Tumor Immunity","volume":"10","author":"Bernard","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Maymand, S., Lakkavaram, A.L., Naser, W., Rasighaemi, P., Dlugolenski, D., Liongue, C., Stambas, J., de Koning-Ward, T.F., and Ward, A.C. (2023). Role of Cytokine-Inducible SH2 Domain-Containing (CISH) Protein in the Regulation of Erythropoiesis. Biomolecules, 13.","DOI":"10.3390\/biom13101510"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Acosta, J.C., Bahr, J.M., Basu, S., O\u2019Donnell, J.T., and Barua, A. (2023). Expression of CISH, an Inhibitor of NK Cell Function, Increases in Association with Ovarian Cancer Development and Progression. Biomedicines, 11.","DOI":"10.3390\/biomedicines11020299"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1158\/2159-8290.CD-15-0944","article-title":"Suppression of Metastases Using a New Lymphocyte Checkpoint Target for Cancer Immunotherapy","volume":"6","author":"Blake","year":"2016","journal-title":"Cancer Discov."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Molfetta, R., Zitti, B., Lecce, M., Milito, N.D., Stabile, H., Fionda, C., Cippitelli, M., Gismondi, A., Santoni, A., and Paolini, R. (2020). CD155: A Multi-Functional Molecule in Tumor Progression. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21030922"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"e1445949","DOI":"10.1080\/2162402X.2018.1445949","article-title":"Deficiency of Host CD96 and PD-1 or TIGIT Enhances Tumor Immunity without Significantly Compromising Immune Homeostasis","volume":"7","author":"Blake","year":"2018","journal-title":"Oncoimmunology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"216381","DOI":"10.1016\/j.canlet.2023.216381","article-title":"CD155 and Its Receptors in Cancer Immune Escape and Immunotherapy","volume":"573","author":"Zhou","year":"2023","journal-title":"Cancer Lett."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1111\/cei.13407","article-title":"TIGIT as an Emerging Immune Checkpoint","volume":"200","author":"Guillerey","year":"2020","journal-title":"Clin. Exp. Immunol."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Feng, S., Isayev, O., Werner, J., and Bazhin, A.V. (2023). CD96 as a Potential Immune Regulator in Cancers. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021303"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Mohammadian Gol, T., Kim, M., Sinn, R., Ure\u00f1a-Bail\u00e9n, G., Stegmeyer, S., Gratz, P.G., Zahedipour, F., Roig-Merino, A., Antony, J.S., and Mezger, M. (2023). CRISPR-Cas9-Based Gene Knockout of Immune Checkpoints in Expanded NK Cells. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242216065"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.1172\/JCI123955","article-title":"Blocking Expression of Inhibitory Receptor NKG2A Overcomes Tumor Resistance to NK Cells","volume":"129","author":"Kamiya","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Kaulfuss, M., Mietz, J., Fabri, A., Vom Berg, J., M\u00fcnz, C., and Chijioke, O. (2023). The NK Cell Checkpoint NKG2A Maintains Expansion Capacity of Human NK Cells. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-37779-6"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"626","DOI":"10.3324\/haematol.2015.135301","article-title":"Effects of Anti-NKG2A Antibody Administration on Leukemia and Normal Hematopoietic Cells","volume":"101","author":"Ruggeri","year":"2016","journal-title":"Haematologica"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1038\/s41392-020-00348-8","article-title":"Immune Checkpoint Molecules in Natural Killer Cells as Potential Targets for Cancer Immunotherapy","volume":"5","author":"Cao","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1038\/s41375-024-02271-1","article-title":"PD-1 Expression Contributes to Functional Impairment of NK Cells in Patients with B-CLL","volume":"38","author":"Farhat","year":"2024","journal-title":"Leukemia"},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Quatrini, L., Mariotti, F.R., Munari, E., Tumino, N., Vacca, P., and Moretta, L. (2020). The Immune Checkpoint PD-1 in Natural Killer Cells: Expression, Function and Targeting in Tumour Immunotherapy. Cancers, 12.","DOI":"10.3390\/cancers12113285"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1186\/s12943-024-02023-w","article-title":"Regulatory Mechanisms of PD-1\/PD-L1 in Cancers","volume":"23","author":"Lin","year":"2024","journal-title":"Mol. Cancer"},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Chen, Y., Wu, S., Guo, G., Fei, L., Guo, S., Yang, C., Fu, X., and Wu, Y. (2011). Programmed Death (PD)-1-Deficient Mice Are Extremely Sensitive to Murine Hepatitis Virus Strain-3 (MHV-3) Infection. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1001347"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"eabj3286","DOI":"10.1126\/sciadv.abj3286","article-title":"When Killers Become Thieves: Trogocytosed PD-1 Inhibits NK Cells in Cancer","volume":"8","author":"Hasim","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2286","DOI":"10.1182\/blood-2010-02-271874","article-title":"The PD-1\/PD-L1 Axis Modulates the Natural Killer Cell Versus Multiple Myeloma Effect: A Therapeutic Target for CT-011, a Novel Monoclonal Anti-PD-1 Antibody","volume":"116","author":"Benson","year":"2010","journal-title":"Blood"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"4654","DOI":"10.1172\/JCI99317","article-title":"Contribution of NK Cells to Immunotherapy Mediated by PD-1\/PD-L1 Blockade","volume":"128","author":"Hsu","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.intimp.2018.06.001","article-title":"Immune Checkpoint Blockade Therapy for Cancer: An Overview of FDA-Approved Immune Checkpoint Inhibitors","volume":"62","author":"Hargadon","year":"2018","journal-title":"Int. Immunopharmacol."},{"key":"ref_114","unstructured":"(2024, November 12). U.S. Food and Drug Administration, Office of the Commissioner, Available online: https:\/\/www.fda.gov\/about-fda\/fda-organization\/office-commissioner."},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Ge, H., Guo, N., Liu, Y., Lang, B., Yin, X., Yu, X., Zhang, Z., Fu, Y., Ding, H., and Hu, Q. (2025). The Inhibitory Receptor LAG3 Affects NK Cell IFN-\u03b3 Production through Glycolysis and the PSAT1\/STAT1\/IFNG Pathway. mBio, 16.","DOI":"10.1128\/mbio.00230-25"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"15330338231202650","DOI":"10.1177\/15330338231202650","article-title":"Clinical Significance of Soluble LAG-3 (sLAG-3) in Patients with Cervical Cancer Determined via Enzyme-Linked Immunosorbent Assay with Monoclonal Antibodies","volume":"22","author":"Li","year":"2023","journal-title":"Technol. Cancer Res. Treat."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Mariuzza, R.A., Shahid, S., and Karade, S.S. (2024). The Immune Checkpoint Receptor LAG3: Structure, Function, and Target for Cancer Immunotherapy. J. Biol. Chem., 300.","DOI":"10.1016\/j.jbc.2024.107241"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s40425-014-0043-z","article-title":"Combined Immune Checkpoint Protein Blockade and Low Dose Whole Body Irradiation as Immunotherapy for Myeloma","volume":"3","author":"Jing","year":"2015","journal-title":"J. Immunother. Cancer"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1186\/s13045-023-01499-1","article-title":"Targeting LAG-3, TIM-3, and TIGIT for Cancer Immunotherapy","volume":"16","author":"Cai","year":"2023","journal-title":"J. Hematol. Oncol."},{"key":"ref_120","first-page":"62","article-title":"Targeting T Cell Checkpoints 41BB and LAG3 and Myeloid Cell CXCR1\/CXCR2 Results in Antitumor Immunity and Durable Response in Pancreatic Cancer","volume":"4","author":"Gulhati","year":"2023","journal-title":"Nat. Cancer"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"200773","DOI":"10.1016\/j.omton.2024.200773","article-title":"Promising Immunotherapy Targets: TIM3, LAG3, and TIGIT Joined the Party","volume":"32","author":"Lu","year":"2024","journal-title":"Mol. Ther. Oncol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1038\/s43018-024-00818-w","article-title":"Clinical Response and Pathway-Specific Correlates Following TIGIT-LAG3 Blockade in Myeloma: The MyCheckpoint Randomized Clinical Trial","volume":"5","author":"Richard","year":"2024","journal-title":"Nat. Cancer"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"3848","DOI":"10.3390\/cimb45050248","article-title":"AhR and Wnt\/\u03b2-Catenin Signaling Pathways and Their Interplay","volume":"45","author":"Grishanova","year":"2023","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1038\/s41577-019-0125-8","article-title":"The Aryl Hydrocarbon Receptor: An Environmental Sensor Integrating Immune Responses in Health and Disease","volume":"19","author":"Rothhammer","year":"2019","journal-title":"Nat. Rev. Immunol."},{"key":"ref_125","doi-asserted-by":"crossref","unstructured":"Grishanova, A.Y., and Perepechaeva, M.L. (2022). Aryl Hydrocarbon Receptor in Oxidative Stress as a Double Agent and Its Biological and Therapeutic Significance. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23126719"},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Liu, S., Wang, M., Xu, L., Deng, D., Lu, L., Tian, J., Zhou, D., and Rui, K. (2025). New Insight into the Role of SOCS Family in Immune Regulation and Autoimmune Pathogenesis. J. Adv. Res., in press.","DOI":"10.1016\/j.jare.2025.05.020"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1186\/s13287-023-03516-z","article-title":"ADSC Secretome Constrains NK Cell Activity by Attenuating IL-2-Mediated JAK-STAT and AKT Signaling Pathway via Upregulation of CIS and DUSP4","volume":"14","author":"Ko","year":"2023","journal-title":"Stem Cell Res. Ther."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.stem.2020.05.008","article-title":"Metabolic Reprograming via Deletion of CISH in Human iPSC-Derived NK Cells Promotes In Vivo Persistence and Enhances Anti-Tumor Activity","volume":"27","author":"Zhu","year":"2020","journal-title":"Cell Stem Cell"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1038\/s41419-023-05961-3","article-title":"TIGIT, a Novel Immune Checkpoint Therapy for Melanoma","volume":"14","author":"Tang","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_130","doi-asserted-by":"crossref","unstructured":"Yue, C., Gao, S., Li, S., Xing, Z., Qian, H., Hu, Y., Wang, W., and Hua, C. (2022). TIGIT as a Promising Therapeutic Target in Autoimmune Diseases. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.911919"},{"key":"ref_131","doi-asserted-by":"crossref","unstructured":"Ge, Z., Peppelenbosch, M.P., Sprengers, D., and Kwekkeboom, J. (2021). TIGIT, the Next Step Towards Successful Combination Immune Checkpoint Therapy in Cancer. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.699895"},{"key":"ref_132","doi-asserted-by":"crossref","unstructured":"Wang, X., Xiong, H., and Ning, Z. (2022). Implications of NKG2A in Immunity and Immune-Mediated Diseases. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.960852"},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"Cazzetta, V., Depierreux, D., Colucci, F., Mikulak, J., and Mavilio, D. (2023). NKG2A Immune Checkpoint in V\u03b42 T Cells: Emerging Application in Cancer Immunotherapy. Cancers, 15.","DOI":"10.3390\/cancers15041264"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"e009934","DOI":"10.1136\/jitc-2024-009934","article-title":"Unlocking the Therapeutic Potential of the NKG2A-HLA-E Immune Checkpoint Pathway in T Cells and NK Cells for Cancer Immunotherapy","volume":"12","author":"Li","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"ref_135","first-page":"727","article-title":"PD-1\/PD-L1 Pathway: Current Researches in Cancer","volume":"10","author":"Han","year":"2020","journal-title":"Am. J. Cancer Res."},{"key":"ref_136","doi-asserted-by":"crossref","unstructured":"Wang, Y., and Wang, Y. (2023). Palmitic Acid Upregulates CD96 Expression to Mediate Maternal\u2013Foetal Interface Immune Tolerance by Inhibiting Cytotoxic Activity and Promoting Adhesion Function in Human Decidual Natural Killer Cells. Bioengineering, 10.","DOI":"10.3390\/bioengineering10091008"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/ni.2850","article-title":"The Receptors CD96 and CD226 Oppose Each Other in the Regulation of Natural Killer Cell Functions","volume":"15","author":"Chan","year":"2014","journal-title":"Nat. Immunol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1111\/imr.12518","article-title":"TIGIT and CD96: New Checkpoint Receptor Targets for Cancer Immunotherapy","volume":"276","author":"Dougall","year":"2017","journal-title":"Immunol. Rev."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"2354","DOI":"10.1016\/j.cell.2025.02.014","article-title":"Ligand-Induced Ubiquitination Unleashes LAG3 Immune Checkpoint Function by Hindering Membrane Sequestration of Signaling Motifs","volume":"188","author":"Jiang","year":"2025","journal-title":"Cell"},{"key":"ref_140","doi-asserted-by":"crossref","unstructured":"Graydon, C.G., Mohideen, S., and Fowke, K.R. (2020). LAG3\u2019s Enigmatic Mechanism of Action. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.615317"},{"key":"ref_141","doi-asserted-by":"crossref","unstructured":"Huo, J.-L., Wang, Y.-T., Fu, W.-J., Lu, N., and Liu, Z.-S. (2022). The Promising Immune Checkpoint LAG-3 in Cancer Immunotherapy: From Basic Research to Clinical Application. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.956090"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.canlet.2021.04.011","article-title":"The TIM3\/Gal9 Signaling Pathway: An Emerging Target for Cancer Immunotherapy","volume":"510","author":"Kandel","year":"2021","journal-title":"Cancer Lett."},{"key":"ref_143","doi-asserted-by":"crossref","unstructured":"Yu, X., Lang, B., Chen, X., Tian, Y., Qian, S., Zhang, Z., Fu, Y., Xu, J., Han, X., and Ding, H. (2021). The Inhibitory Receptor Tim-3 Fails to Suppress IFN-\u03b3 Production via the NFAT Pathway in NK-Cell, Unlike That in CD4+ T Cells. BMC Immunol., 22.","DOI":"10.1186\/s12865-021-00417-9"},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Wang, C., Liu, J., Wu, Q., Wang, Z., Hu, B., and Bo, L. (2024). The Role of TIM-3 in Sepsis: A Promising Target for Immunotherapy?. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1328667"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/s41577-019-0224-6","article-title":"TIM3 Comes of Age as an Inhibitory Receptor","volume":"20","author":"Wolf","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"101712","DOI":"10.1016\/j.smim.2023.101712","article-title":"IL-1R8: A Molecular Brake of Anti-Tumor and Anti-Viral Activity of NK Cells and ILC","volume":"66","author":"Mariotti","year":"2023","journal-title":"Semin. Immunol."},{"key":"ref_147","doi-asserted-by":"crossref","unstructured":"Supino, D., Minute, L., Mariancini, A., Riva, F., Magrini, E., and Garlanda, C. (2022). Negative Regulation of the IL-1 System by IL-1R2 and IL-1R8: Relevance in Pathophysiology and Disease. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.804641"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"e003858","DOI":"10.1136\/jitc-2021-003858","article-title":"IL-1R8 Silencing Improves the Anti-Tumor Function of Freshly Isolated Human NK Cells","volume":"10","author":"Landolina","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/nature24293","article-title":"IL-1R8 Is a Checkpoint in NK Cells Regulating Anti-Tumour and Anti-Viral Activity","volume":"551","author":"Molgora","year":"2017","journal-title":"Nature"},{"key":"ref_150","doi-asserted-by":"crossref","unstructured":"Sun, H., and Sun, C. (2019). The Rise of NK Cell Checkpoints as Promising Therapeutic Targets in Cancer Immunotherapy. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.02354"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"eadh4379","DOI":"10.1126\/sciadv.adh4379","article-title":"Siglec-7 Glyco-Immune Binding mAbs or NK Cell Engager Biologics Induce Potent Antitumor Immunity Against Ovarian Cancers","volume":"9","author":"Bordoloi","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s40164-025-00633-8","article-title":"The Clinical Landscape of CAR NK Cells","volume":"14","author":"Christensen","year":"2025","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_153","doi-asserted-by":"crossref","unstructured":"G\u0142owacki, P., and Rieske, P. (2022). Application and Design of Switches Used in CAR. Cells, 11.","DOI":"10.3390\/cells11121910"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"23996","DOI":"10.18632\/oncotarget.15098","article-title":"Caspase-9: Structure, Mechanisms and Clinical Application","volume":"8","author":"Li","year":"2017","journal-title":"Oncotarget"},{"key":"ref_155","doi-asserted-by":"crossref","unstructured":"Gargett, T., and Brown, M.P. (2014). The Inducible Caspase-9 Suicide Gene System as a \u201cSafety Switch\u201d to Limit on-Target, off-Tumor Toxicities of Chimeric Antigen Receptor T Cells. Front. Pharmacol., 5.","DOI":"10.3389\/fphar.2014.00235"},{"key":"ref_156","doi-asserted-by":"crossref","unstructured":"Shabaneh, T.B., Moffett, H.F., Stull, S.M., Derezes, T., Tait, L.J., Park, S., Riddell, S.R., and Lajoie, M.J. (2022). Safety Switch Optimization Enhances Antibody-Mediated Elimination of CAR T Cells. Front. Mol. Med., 2.","DOI":"10.3389\/fmmed.2022.1026474"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.coi.2021.07.002","article-title":"Safety Switches for Adoptive Cell Therapy","volume":"74","author":"Sahillioglu","year":"2022","journal-title":"Curr. Opin. Immunol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1186\/s12967-023-04041-6","article-title":"Tuning CARs: Recent Advances in Modulating Chimeric Antigen Receptor (CAR) T Cell Activity for Improved Safety, Efficacy, and Flexibility","volume":"21","author":"Celichowski","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"eadj6251","DOI":"10.1126\/sciadv.adj6251","article-title":"Enhancing the Safety of CAR-T Cell Therapy: Synthetic Genetic Switch for Spatiotemporal Control","volume":"10","author":"Lu","year":"2024","journal-title":"Sci. Adv."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1158\/1078-0432.CCR-23-2566","article-title":"TROP2 Is Associated with Primary Resistance to Immune Checkpoint Inhibition in Patients with Advanced Non\u2013Small Cell Lung Cancer","volume":"30","author":"Bessede","year":"2024","journal-title":"Clin. Cancer Res."},{"key":"ref_161","doi-asserted-by":"crossref","unstructured":"El Achi, H., Dupont, E., Paul, S., and Khoury, J.D. (2020). CD123 as a Biomarker in Hematolymphoid Malignancies: Principles of Detection and Targeted Therapies. Cancers, 12.","DOI":"10.3390\/cancers12113087"},{"key":"ref_162","doi-asserted-by":"crossref","unstructured":"Pelosi, E., Castelli, G., and Testa, U. (2023). CD123 a Therapeutic Target for Acute Myeloid Leukemia and Blastic Plasmocytoid Dendritic Neoplasm. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032718"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"101002","DOI":"10.1016\/j.blre.2022.101002","article-title":"Targeting CD19 for Diffuse Large B Cell Lymphoma in the Era of CARs: Other Modes of Transportation","volume":"57","author":"Sermer","year":"2023","journal-title":"Blood Rev."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41408-020-0337-y","article-title":"B-Cell Maturation Antigen Expression across Hematologic Cancers: A Systematic Literature Review","volume":"10","author":"Dogan","year":"2020","journal-title":"Blood Cancer J."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1182\/blood.2020008221","article-title":"CD70-Specific CAR T Cells Have Potent Activity against Acute Myeloid Leukemia Without HSC Toxicity","volume":"138","author":"Sauer","year":"2021","journal-title":"Blood"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1186\/s13045-023-01464-y","article-title":"Emerging Therapies Targeting the Delta-like Ligand 3 (DLL3) in Small Cell Lung Cancer","volume":"16","author":"Rudin","year":"2023","journal-title":"J. Hematol. Oncol."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/s12943-024-02012-z","article-title":"DLL3-Guided Therapies in Small-Cell Lung Cancer: From Antibody-Drug Conjugate to Precision Immunotherapy and Radioimmunotherapy","volume":"23","author":"Su","year":"2024","journal-title":"Mol. Cancer"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1016\/j.bulcan.2022.08.001","article-title":"MUC1: An Emerging Target in Cancer Treatment and Diagnosis","volume":"109","author":"Qing","year":"2022","journal-title":"Bull. Cancer"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1007\/s00262-016-1917-3","article-title":"5T4 Oncofoetal Antigen: An Attractive Target for Immune Intervention in Cancer","volume":"66","author":"Stern","year":"2016","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"e15005","DOI":"10.1200\/JCO.2024.42.16_suppl.e15005","article-title":"Preclinical Studies of an Innovative 5T4-ADC ACR246 with the Potential to Better Treat 5T4-Positive Solid Tumors","volume":"42","author":"Huang","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1158\/1535-7163.MCT-24-0052","article-title":"Targeting Tumor Antigen 5T4 Using CAR T Cells for the Treatment of Acute Myeloid Leukemia","volume":"24","author":"Harrop","year":"2025","journal-title":"Mol. Cancer Ther."},{"key":"ref_172","doi-asserted-by":"crossref","unstructured":"Zheng, X., Liu, X., Lei, Y., Wang, G., and Liu, M. (2022). Glypican-3: A Novel and Promising Target for the Treatment of Hepatocellular Carcinoma. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.824208"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.7150\/jca.39972","article-title":"Glypican-3: A New Target for Diagnosis and Treatment of Hepatocellular Carcinoma","volume":"11","author":"Guo","year":"2020","journal-title":"J. Cancer"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"437","DOI":"10.3324\/haematol.2020.271908","article-title":"CD38 Knockout Natural Killer Cells Expressing an Affinity Optimized CD38 Chimeric Antigen Receptor Successfully Target Acute Myeloid Leukemia with Reduced Effector Cell Fratricide","volume":"107","author":"Gurney","year":"2022","journal-title":"Haematologica"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1007\/s00262-008-0585-3","article-title":"Clinical Significance of the NKG2D Ligands, MICA\/B and ULBP2 in Ovarian Cancer: High Expression of ULBP2 Is an Indicator of Poor Prognosis","volume":"58","author":"Li","year":"2008","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1038\/bjc.2017.79","article-title":"MHC Class I Chain-Related Protein A and B (MICA and MICB) Are Predominantly Expressed Intracellularly in Tumour and Normal Tissue","volume":"116","author":"Ghadially","year":"2017","journal-title":"Br. J. Cancer"},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"1758835919855238","DOI":"10.1177\/1758835919855238","article-title":"Targeting the SLIT\/ROBO Pathway in Tumor Progression: Molecular Mechanisms and Therapeutic Perspectives","volume":"11","author":"Jiang","year":"2019","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"2956","DOI":"10.21037\/gs-21-406","article-title":"ROBO1 Protein Expression Is Independently Associated with Biochemical Recurrence in Prostate Cancer Patients Who Underwent Radical Prostatectomy in Asian Patients","volume":"10","author":"Kim","year":"2021","journal-title":"Gland. Surg."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1517\/14728222.2014.909413","article-title":"The Role of CD33 as Therapeutic Target in Acute Myeloid Leukemia","volume":"18","author":"Walter","year":"2014","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1016\/j.immuni.2021.06.008","article-title":"The Chemokine CCL1 Triggers an AMFR-SPRY1 Pathway That Promotes Differentiation of Lung Fibroblasts into Myofibroblasts and Drives Pulmonary Fibrosis","volume":"54","author":"Liu","year":"2021","journal-title":"Immunity"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/s41408-023-00966-9","article-title":"GPRC5D as a Novel Target for the Treatment of Multiple Myeloma: A Narrative Review","volume":"14","author":"Pillarisetti","year":"2024","journal-title":"Blood Cancer J."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41571-020-0403-1","article-title":"TGF\u03b2 Biology in Cancer Progression and Immunotherapy","volume":"18","author":"Derynck","year":"2021","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1186\/s12967-023-04560-2","article-title":"Knockdown of NR3C1 Inhibits the Proliferation and Migration of Clear Cell Renal Cell Carcinoma through Activating Endoplasmic Reticulum Stress\u2013Mitophagy","volume":"21","author":"Yan","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.cellimm.2012.02.014","article-title":"Glucocorticoid Receptor Mediated Suppression of Natural Killer Cell Activity: Identification of Associated Deacetylase and Corepressor Molecules","volume":"275","author":"Bush","year":"2012","journal-title":"Cell Immunol."},{"key":"ref_185","doi-asserted-by":"crossref","unstructured":"Krug, A., Martinez-Turtos, A., and Verhoeyen, E. (2021). Importance of T, NK, CAR T and CAR NK Cell Metabolic Fitness for Effective Anti-Cancer Therapy: A Continuous Learning Process Allowing the Optimization of T, NK and CAR-Based Anti-Cancer Therapies. Cancers, 14.","DOI":"10.3390\/cancers14010183"},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"e95128","DOI":"10.1172\/jci.insight.95128","article-title":"Glycolytic Requirement for NK Cell Cytotoxicity and Cytomegalovirus Control","volume":"2","author":"Mah","year":"2017","journal-title":"JCI Insight"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.omtm.2020.06.014","article-title":"Superior Expansion and Cytotoxicity of Human Primary NK and CAR-NK Cells from Various Sources via Enriched Metabolic Pathways","volume":"18","author":"Yang","year":"2020","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"4745","DOI":"10.1158\/1078-0432.CCR-25-1693","article-title":"The Activity of EGFR CAR NK and CAR T Cells Against EGFR Inhibitor\u2013Resistant NSCLC and Drug-Tolerant Persister Cells","volume":"31","author":"Yang","year":"2025","journal-title":"Clin. Cancer Res."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"200927","DOI":"10.1016\/j.omton.2024.200927","article-title":"Combinatorial Immunotherapy with Anti-ROR1 CAR NK Cells and an IL-21 Secreting Oncolytic Virus Against Neuroblastoma","volume":"33","author":"Chu","year":"2025","journal-title":"Mol. Ther. Oncol."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"2054105","DOI":"10.1080\/2162402X.2022.2054105","article-title":"STING Agonist cGAMP Enhances Anti-Tumor Activity of CAR-NK Cells Against Pancreatic Cancer","volume":"11","author":"Da","year":"2022","journal-title":"OncoImmunology"},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"e901","DOI":"10.1002\/ctm2.901","article-title":"Combined Treatment with anti-PSMA CAR NK-92 Cell and Anti-PD-L1 Monoclonal Antibody Enhances the Antitumour Efficacy Against Castration-Resistant Prostate Cancer","volume":"12","author":"Wang","year":"2022","journal-title":"Clin. Transl. Med."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1158\/2159-8290.CD-18-1259","article-title":"The Mechanism of Anti-PD-L1 Antibody Efficacy Against PD-L1 Negative Tumors Identifies NK Cells Expressing PD-L1 as a Cytolytic Effector","volume":"9","author":"Dong","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_193","doi-asserted-by":"crossref","unstructured":"Yang, L., Shen, M., Xu, L.J., Yang, X., Tsai, Y., Keng, P.C., Chen, Y., and Lee, S.O. (2017). Enhancing NK Cell-Mediated Cytotoxicity to Cisplatin-Resistant Lung Cancer Cells via MEK\/Erk Signaling Inhibition. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-08483-z"},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s00262-025-04196-9","article-title":"NKG2D CAR-NK Adoptive Cellular Immunotherapy Combined with or without PD-1 Blockade in the Treatment of Patients with Metastatic Colorectal Cancer: An Exploratory Study","volume":"74","author":"Wang","year":"2025","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/s12032-023-02051-4","article-title":"Implications of IL-21 in Solid Tumor Therapy","volume":"40","author":"Eivary","year":"2023","journal-title":"Med. Oncol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/23\/1858\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T15:45:47Z","timestamp":1764085547000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/23\/1858"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,25]]},"references-count":195,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["cells14231858"],"URL":"https:\/\/doi.org\/10.3390\/cells14231858","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,25]]}}}