Natural Killer and CAR-NK immunotherapy in breast cancer: bridging promise and the solid-tumor barrier

Abstract Breast cancer (BC) represents an immunotherapy paradox: despite the development of precise immune engineering protocols in hematologic malignancies, metastatic BC rarely becomes curable, and long-term immune control is uncommon. Natural killer (NK) cells, particularly chimeric antigen receptor (CAR)-modified NK cells, offer a pragmatic alternative to T cell–centric adoptive platforms because NK cells combine innate “missing-self/induced-self” recognition with antibody-dependent cell-mediated cytotoxicity (ADCC) and can be employed in allogeneic, “off-the-shelf” formats. However, the obstacles that blunt NK cell efficacy in solid tumors are not primarily about whether NK cells can kill BC cells in vitro . There is a concern about whether NK cells can access tumor nests, persist long enough, and remain functional within the suppressive and metabolically aggressive tumor microenvironment (TME). Here, we synthesize key biological and translational limitation points as phenotype alteration during manufacturing (including loss of CD16/ADCC competence), licensing and donor KIR/HLA variables, TGF-β and cytokine-driven paralysis, metabolic mismatch, and limited persistence of CAR–NK cells, and propose a BC-focused experimental approach. Priorities include, i) NK cell-engineering and CAR design optimization to enhance efficacy of antibody-based therapy of BC, ii) manufacturing standardization and quality metrics, iii) BC TME modulation, combination strategies and treating trafficking as a first-class endpoint, v) pairing NK cells with rational partners (antibodies, engagers, NK cell checkpoints), and vi) redesigning early trials around immune-functional endpoints that reflect BC metastatic biology.