CELL INTELLIGENCE · 肿瘤细胞治疗研究

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 and risk of bias (RoB) was assessed using SYRCLE's 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 5-10 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 [0.22-0.44] and 0.42 [0.33-0.53], p < 0.001, respectively). Survival was also prolonged significantly (MSR 1.47 [1.15-1.87], p = 0.010 vs. untreated; 1.30 [1.09-1.60], p = 0.007 vs. unmodified/mock NK cells). Subgroup analyses indicated improved efficacy with peripheral blood source and 5-10 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.