Engineering CAR-NK cell platforms for breast cancer: metastatic interception, perioperative control, and emerging platelet-guided biomimetic strategies

Breast cancer metastasis remains the leading cause of disease-related mortality, highlighting the need for strategies that can intercept circulating tumor cells, suppress micrometastatic outgrowth, and eliminate residual disease during the perioperative window. Although CAR-T cell therapy has transformed hematologic oncology, its translation to breast cancer has been constrained by toxicity, poor solid-tumor infiltration, antigen heterogeneity, and manufacturing complexity. In this context, CAR-NK cells have emerged as a compelling translational platform that combines antigen-directed cytotoxicity with intrinsic HLA-independent killing, reduced alloreactivity, and the feasibility of scalable off-the-shelf production. This review develops a breast cancer-specific conceptual framework in which CAR-NK cells are positioned not only as direct effector cells but also as programmable innate immune tools for metastatic niche control, interception of circulating tumor cells, and perioperative immune reprogramming. We synthesize evidence showing that breast tumors evade NK-cell surveillance through checkpoint signaling, ligand shedding, stromal exclusion, metabolic stress, and defective trafficking. At the same time, HER2 and TROP2 remain the most actionable near-term targets, and EpCAM, MUC1, EGFR, and B7-H3 represent important emerging candidates for biomarker-guided and multi-antigen strategies. A major conceptual advance of this review is the integration of CAR-NK therapy into the perioperative window, a biologically vulnerable period marked by surgical stress, neuroendocrine activation, wound-healing programs, and transient NK-cell suppression that may promote metastatic resurgence. We further introduce platelet-guided CAR-NK exosome hybridization as a testable sequential targeting strategy intended to combine platelet-mediated enrichment on circulating tumor cells with subsequent CAR-dependent tumor recognition and cytotoxic payload delivery. In parallel, we highlight biomaterial-guided delivery, particularly injectable and implantable hydrogels, as an innovative approach to localize CAR-NK cells, prolong retention, protect effector function, and convert the resection cavity into an active immunologic depot. Collectively, this review proposes a translational roadmap in which CAR-NK therapy, platelet-enabled circulating tumor cell targeting, biomaterial-assisted delivery, and perioperative intervention converge to redefine metastatic and postoperative disease control in breast cancer.