{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T19:32:38Z","timestamp":1787513558147,"version":"build-2736575974"},"reference-count":39,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Ohio State University Comprehensive Cancer Center Intramural Research Program","award":["IRP00915"],"award-info":[{"award-number":["IRP00915"]}]},{"name":"The Ohio State University Comprehensive Cancer Center Intramural Research Program","award":["IRP01207"],"award-info":[{"award-number":["IRP01207"]}]},{"award":["IRP00915"],"award-info":[{"award-number":["IRP00915"]}],"id":[{"id":"https:\/\/ror.org\/028t46f04","id-type":"ROR","asserted-by":"publisher"}]},{"award":["IRP01207"],"award-info":[{"award-number":["IRP01207"]}],"id":[{"id":"https:\/\/ror.org\/028t46f04","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: For almost two decades now, chimeric antigen receptor-natural killer cells (CAR-NK) have been investigated in pre-clinical breast cancer models, yet clinical evidence on efficacy remains scarce. This meta-analysis provides pooled evidence of pre-clinical CAR-NK effectiveness and safety in breast cancer and an overview of current clinical trials to support clinical translation. Methods: Following PRISMA guidelines and a registered protocol (PROSPERO, CRD420251131530), PubMed, Web of Science, and Scopus were searched up to 30 June 2025 for pre-clinical CAR-NK studies in breast cancer. Clinical studies were retrieved from clinicaltrials.gov and the International Clinical Trial Registry Platform (ICTRP) up to 1 March 2026. Pre-clinical studies without in vivo data or non-human CAR-NK cells were excluded. Primary outcomes were tumor burden (ratio of means, ROMs) and survival (median survival ratio, MSR). Data were analyzed in JASP\u2122 and risk of bias (RoB) was assessed using SYRCLE\u2019s tool. Results: Fourteen pre-clinical studies (38 CAR-NK treatment groups targeting EGFR, HER2, tissue factor, CD70, mesothelin, or folate receptor, with peripheral blood as the primary NK source, and a 5\u201310 million cell dose) and 11 early-phase clinical studies (targeting HER2, TROP2, PD-L1, MUC1, or NKG2D ligands under ongoing investigation) were included. In pooled pre-clinical analysis, CAR-NK significantly reduced tumor burden against untreated and unmodified\/mock controls (ROM 0.311 [0.22\u20130.44] and 0.42 [0.33\u20130.53], p &lt; 0.001, respectively). Survival was also prolonged significantly (MSR 1.47 [1.15\u20131.87], p = 0.010 vs. untreated; 1.30 [1.09\u20131.60], p = 0.007 vs. unmodified\/mock NK cells). Subgroup analyses indicated improved efficacy with peripheral blood source and 5\u201310 M dosing. No treatment-related toxicities were reported. CAR-NK persistence was generally higher than unmodified\/mock NK cells. Discussion and Conclusions: Significant heterogeneity was observed in ROM analysis which the multi-level meta-analysis configured as intra-study interventional variability. There was moderate RoB in pre-clinical studies. Published results from clinical trials remain limited, highlighting early stages of investigation. Overall, CAR-NK therapy demonstrated consistent pre-clinical efficacy and safety, supporting further translational and clinical evaluation in breast cancer.<\/jats:p>","DOI":"10.3390\/cancers18101634","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T11:53:10Z","timestamp":1779191590000},"page":"1634","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Evaluation of Efficacy and Safety of Chimeric Antigen Receptor-Natural Killer (CAR-NK) Cells in Breast Cancer: A Systematic Review and Meta-Analysis"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7550-213X","authenticated-orcid":false,"given":"Nabeel","family":"Ahmed","sequence":"first","affiliation":[{"name":"Yunnan Key Laboratory of Plateau Thermal Medical Rehabilitation and Wellness, School of Rehabilitation, Kunming Medical University, Kunming 650500, China"},{"name":"School of Pharmacy, Kunming Medical University, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jawaria","family":"Jabeen","sequence":"additional","affiliation":[{"name":"College of Pharmacy, University of Sargodha, Sargodha 40100, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Safa","family":"Noor","sequence":"additional","affiliation":[{"name":"College of Pharmacy, University of Sargodha, Sargodha 40100, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0524-1941","authenticated-orcid":false,"given":"Malja","family":"Rehman","sequence":"additional","affiliation":[{"name":"College of Pharmacy, University of Sargodha, Sargodha 40100, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sana","family":"Tahseen","sequence":"additional","affiliation":[{"name":"Punjab University College of Pharmacy, University of the Punjab, Lahore 54000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmaa","family":"Qamar","sequence":"additional","affiliation":[{"name":"College of Pharmacy, University of Sargodha, Sargodha 40100, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Anas","sequence":"additional","affiliation":[{"name":"College of Pharmacy, University of Sargodha, Sargodha 40100, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Muneeb","family":"Khalid","sequence":"additional","affiliation":[{"name":"College of Pharmacy, University of Sargodha, Sargodha 40100, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Li","sequence":"additional","affiliation":[{"name":"Cancer Biotherapy Center & Cancer Research Institute, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming 650106, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lechun","family":"Lyu","sequence":"additional","affiliation":[{"name":"Yunnan Key Laboratory of Plateau Thermal Medical Rehabilitation and Wellness, School of Rehabilitation, Kunming Medical University, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0023-1170","authenticated-orcid":false,"given":"Zhiwei","family":"Hu","sequence":"additional","affiliation":[{"name":"Pelotonia Institute for Immuno-Oncology Center for Antibody Therapeutics, The Arthur G. James Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3559","DOI":"10.1016\/j.ymthe.2025.04.033","article-title":"ErbB2\/HER2-Targeted CAR-NK Cells Eliminate Breast Cancer Cells in an Organoid Model That Recapitulates Tumor Progression","volume":"33","author":"Alekseeva","year":"2025","journal-title":"Mol. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Roheel, A., Khan, A., Anwar, F., Akbar, Z., Akhtar, M.F., Imran Khan, M., Sohail, M.F., and Ahmad, R. (2023). Global Epidemiology of Breast Cancer Based on Risk Factors: A Systematic Review. Front. 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