{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T17:49:59Z","timestamp":1790099399496,"version":"4.0.1"},"reference-count":129,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:00:00Z","timestamp":1776211200000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cell Biology International"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Over the past decade, chimeric antigen receptor (CAR) T\u2010cell therapy has revolutionized cancer immunotherapy, demonstrating remarkable efficacy in treating relapsed or refractory hematologic malignancies across both pediatric and adult populations. In parallel, CAR\u2010engineered natural killer (CAR\u2010NK) cells have emerged as a complementary and promising alternative to CAR\u2010T therapy, offering several inherent advantages. Unlike CAR\u2010T cells, CAR\u2010NK cells operate independently of major histocompatibility complex (MHC) compatibility and are associated with a lower risk of adverse immune reactions. They also provide practical benefits, such as the potential for standardized, \u201coff\u2010the\u2010shelf\u201d therapeutic formulations. Consistent and encouraging outcomes have been reported with CAR\u2010NK cell therapy in hematologic cancers; however, their success against solid tumors remains constrained by multiple challenges, including limited tumor infiltration, suboptimal trafficking, and the immunosuppressive characteristics of the tumor microenvironment. Importantly, lung cancer presents indication\u2010specific barriers to cellular immunotherapy, including profound inter and intratumoral heterogeneity, a highly immunosuppressive pulmonary tumor microenvironment, and a narrow safety margin in a vital organ where inflammation or edema can rapidly impair gas exchange. These factors limit the depth and durability of responses achieved with current systemic modalities in a substantial fraction of patients and also constrain adoptive cell therapy in thoracic malignancies. Therefore, lung cancer represents both a compelling and stringent setting to develop safer and more durable engineered cellular platforms such as CAR\u2010NK cells. Lung cancer, one of the most prevalent and lethal malignancies worldwide, still depends largely on conventional treatment modalities such as surgery, chemotherapy, radiotherapy, and targeted agents. Accordingly, we organize this review around lung cancer\u2013specific design constraints, antigen heterogeneity\/escape, impaired trafficking into pulmonary tumors, an immunosuppressive lung microenvironment, and a narrow pulmonary safety window, and map each constraint to actionable CAR\u2010NK engineering and combination strategies.<\/jats:p>","DOI":"10.1002\/cbin.70152","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T11:28:36Z","timestamp":1776252516000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["CAR\u2010NK Cell Biology and Engineering for Solid Tumors, With a Focus on Lung Cancer"],"prefix":"10.1002","volume":"50","author":[{"given":"Xiao","family":"Lyu","sequence":"first","affiliation":[{"name":"Department of Medical Oncology Zibo Central Hospital Zibo Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Oncology Yantaishan Hospital Affiliated to Binzhou Medical University Yantai Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1266-1067","authenticated-orcid":false,"given":"Ruijuan","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Oncology Yantaishan Hospital Affiliated to Binzhou Medical University Yantai Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jurbek","family":"Yuldasheyv","sequence":"additional","affiliation":[{"name":"Department of Clinical Science Urgench state university Urgench Uzbekistan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2013.11.030"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.10.014"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1101\/sqb.2013.78.019869"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/sctm.20-0459"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00909"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.03.024"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.2147\/ITT.S291767"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-76051-z"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.23239"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.Can-13-3583"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.73699"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0192161"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2022.10.010"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00030.2015"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-019-0770-2"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2014.02.003"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.913215"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.888313"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.15326\/jcopdf.2022.0296"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.02.029"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.Can-12-3832"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2018.03.013"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1097\/PPO.0000000000000156"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djy060"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1159\/000487440"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/inorganics12120331"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.609762"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/cns.14489"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.24976\/Discov.Med.202335176.41"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1801005"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2021.4932"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2014.00235"},{"key":"e_1_2_13_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2020.03.017"},{"key":"e_1_2_13_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-021-01083-5"},{"key":"e_1_2_13_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201646559"},{"key":"e_1_2_13_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.2910160205"},{"key":"e_1_2_13_38_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2024-009410"},{"key":"e_1_2_13_39_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.12-2359"},{"key":"e_1_2_13_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2015.08.011"},{"key":"e_1_2_13_41_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.14434"},{"key":"e_1_2_13_42_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1616288"},{"key":"e_1_2_13_43_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2018.00530"},{"key":"e_1_2_13_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2023.03.006"},{"key":"e_1_2_13_45_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40364-020-00228-x"},{"key":"e_1_2_13_46_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-13-1862"},{"key":"e_1_2_13_47_1","doi-asserted-by":"publisher","DOI":"10.1093\/jjco\/hyp181"},{"key":"e_1_2_13_48_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.707542"},{"key":"e_1_2_13_49_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom15070935"},{"key":"e_1_2_13_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2022.105603"},{"key":"e_1_2_13_51_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1384039"},{"key":"e_1_2_13_52_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-017-0275-9"},{"key":"e_1_2_13_53_1","first-page":"73","article-title":"Natural Killer Cells: Role in Local Tumor Growth and Metastasis","volume":"6","author":"Langers I.","year":"2012","journal-title":"Biologics: Targets & Therapy"},{"key":"e_1_2_13_54_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2112431"},{"key":"e_1_2_13_55_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI132712"},{"key":"e_1_2_13_56_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1910607"},{"key":"e_1_2_13_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2017.226"},{"issue":"10","key":"e_1_2_13_58_1","first-page":"2064","article-title":"Role of NKG2D and Its Ligands in Cancer Immunotherapy","volume":"9","author":"Liu H.","year":"2019","journal-title":"American Journal of Cancer Research"},{"key":"e_1_2_13_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2024.101751"},{"key":"e_1_2_13_60_1","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.5MA0122-467R"},{"key":"e_1_2_13_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcyt.2020.06.003"},{"key":"e_1_2_13_62_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.Can-15-0159"},{"key":"e_1_2_13_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.03.018"},{"key":"e_1_2_13_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/0167-5699(90)90097-S"},{"key":"e_1_2_13_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2020.04.016"},{"key":"e_1_2_13_66_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa040938"},{"key":"e_1_2_13_67_1","doi-asserted-by":"publisher","DOI":"10.3390\/cimb45110566"},{"key":"e_1_2_13_68_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18091868"},{"key":"e_1_2_13_69_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00262"},{"key":"e_1_2_13_70_1","doi-asserted-by":"publisher","DOI":"10.4103\/0971-5916.191738"},{"key":"e_1_2_13_71_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1502570"},{"key":"e_1_2_13_72_1","article-title":"Dextran Enhances the Lentiviral Transduction Efficiency of Murine and Human Primary NK Cells","volume":"131","author":"Nanbakhsh A.","year":"2018","journal-title":"Journal of Visualized Experiments"},{"key":"e_1_2_13_73_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omto.2019.12.006"},{"key":"e_1_2_13_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.05.001"},{"key":"e_1_2_13_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2020.119513"},{"key":"e_1_2_13_76_1","doi-asserted-by":"publisher","DOI":"10.25259\/Cytojournal_115_2024"},{"issue":"10","key":"e_1_2_13_77_1","first-page":"3645","article-title":"HER\u20102\/Neu Alterations in Non\u2010Small Cell Lung Cancer: A Comprehensive Evaluation by Real Time Reverse Transcription\u2010PCR, Fluorescence in Situ Hybridization, and Immunohistochemistry","volume":"9","author":"Pellegrini C.","year":"2003","journal-title":"Clinical Cancer Research"},{"key":"e_1_2_13_78_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2023.106656"},{"key":"e_1_2_13_79_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.10.015"},{"key":"e_1_2_13_80_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.05.014"},{"key":"e_1_2_13_81_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-019-0613-7"},{"key":"e_1_2_13_82_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2006.03.003"},{"key":"e_1_2_13_83_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1606774"},{"key":"e_1_2_13_84_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00311"},{"key":"e_1_2_13_85_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2025.1759796"},{"key":"e_1_2_13_86_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1470-2045(16)30565-4"},{"key":"e_1_2_13_87_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-001054"},{"key":"e_1_2_13_88_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2023-008566"},{"key":"e_1_2_13_89_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-07-592881"},{"key":"e_1_2_13_90_1","doi-asserted-by":"publisher","DOI":"10.1002\/sctm.20-0007"},{"key":"e_1_2_13_91_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-018-0343-9"},{"key":"e_1_2_13_92_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.02156"},{"key":"e_1_2_13_93_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c02171"},{"key":"e_1_2_13_94_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2014.01.010"},{"key":"e_1_2_13_95_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1713137"},{"key":"e_1_2_13_96_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-013-1403-0"},{"key":"e_1_2_13_97_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1106152"},{"key":"e_1_2_13_98_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep26157"},{"key":"e_1_2_13_99_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.113993"},{"key":"e_1_2_13_100_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2024.113392"},{"key":"e_1_2_13_101_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3044"},{"key":"e_1_2_13_102_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00408-021-00486-y"},{"key":"e_1_2_13_103_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.884648"},{"key":"e_1_2_13_104_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11404"},{"key":"e_1_2_13_105_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13385"},{"key":"e_1_2_13_106_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2012.00344"},{"key":"e_1_2_13_107_1","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.120.242958"},{"key":"e_1_2_13_108_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri911"},{"key":"e_1_2_13_109_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-020-02558-z"},{"key":"e_1_2_13_110_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-024-02446-2"},{"key":"e_1_2_13_111_1","doi-asserted-by":"publisher","DOI":"10.21037\/tlcr.2019.04.09"},{"key":"e_1_2_13_112_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1103478"},{"key":"e_1_2_13_113_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1901"},{"key":"e_1_2_13_114_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-018-0441-8"},{"key":"e_1_2_13_115_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocp.2019.01.034"},{"key":"e_1_2_13_116_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2019.11.033"},{"key":"e_1_2_13_117_1","doi-asserted-by":"publisher","DOI":"10.25259\/Cytojournal_99_2024"},{"key":"e_1_2_13_118_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2022.106344"},{"key":"e_1_2_13_119_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.19204"},{"key":"e_1_2_13_120_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2020.102975"},{"key":"e_1_2_13_121_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.5361"},{"key":"e_1_2_13_122_1","doi-asserted-by":"publisher","DOI":"10.1002\/smll.202101397"},{"key":"e_1_2_13_123_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.01089"},{"key":"e_1_2_13_124_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2020.06.014"},{"key":"e_1_2_13_125_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.Can-17-2826"},{"key":"e_1_2_13_126_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00533"},{"key":"e_1_2_13_127_1","doi-asserted-by":"publisher","DOI":"10.2147\/JIR.S499403"},{"key":"e_1_2_13_128_1","doi-asserted-by":"publisher","DOI":"10.1177\/09636897221094244"},{"key":"e_1_2_13_129_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2007.02573.x"},{"key":"e_1_2_13_130_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.584099"}],"container-title":["Cell Biology International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cbin.70152","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cbin.70152","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cbin.70152","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T06:53:07Z","timestamp":1776408787000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cbin.70152"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4]]},"references-count":129,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1002\/cbin.70152"],"URL":"https:\/\/doi.org\/10.1002\/cbin.70152","archive":["Portico"],"relation":{},"ISSN":["1065-6995","1095-8355"],"issn-type":[{"value":"1065-6995","type":"print"},{"value":"1095-8355","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4]]},"assertion":[{"value":"2025-12-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70152"}}