Characterization and ex vivo functional properties of NKG2C+ NK cells with adaptive features in breast tumors

Introduction Adaptive Natural Killer cells are a specialized NK-cell subset with enhanced antibody-dependent effector functions, making them attractive candidates for cancer immunotherapy. Although circulating adaptive NK cells have demonstrated potent antitumor activity, their presence and functional status within the breast tumor microenvironment (TME) remain largely unknown. Methods Here, we investigated the infiltration, phenotype, functional properties, and clinical relevance of NKG2C + NK cells with adaptive features (aNK) in treatment-naïve breast cancer. Using paired peripheral blood, tumor, and adjacent non-tumoral breast tissue samples, together with functional assays and transcriptomic analyses from The Cancer Genome Atlas (TCGA), we characterized tumor-infiltrating aNK cells and evaluated their association with clinical outcome. Results aNK cells are present within breast tumors while preserving their phenotype and enhanced effector functions. Tumor-infiltrating aNK cells retained robust antibody-dependent degranulation and IFN-γ production. Complementary studies using peripheral blood-derived aNK cells further demonstrated their superior capacity to promote dendritic cell maturation, supporting their immunoregulatory potential. Moreover, we analyzed an adaptive NK-associated transcriptional signature in TCGA breast cancer samples and found that higher signature scores were associated with a longer progression-free interval and an immune microenvironment enriched in specific CD8 + T-cell populations. Discussion These findings indicate that aNK cells are functionally resilient to the suppressive breast TME, maintaining some specialized functions and immunoregulatory properties after tumor infiltration. Their persistence and association with favorable clinical outcome provide a rationale for further investigating their potential role in antibody-based immunotherapy and as a possible target for therapeutic strategies in BC.