Adaptive NK Cells Exhibit Tumor-Specific Immune Memory and Cytotoxicity in Ovarian Cancer

Abstract Adaptive Natural Killer (aNK) cells have emerged as a subset of NK cells with memory-like properties and specific cytotoxicity, offering promising therapeutic potential in cancer immunotherapy. In this study, we explored the role of aNK cells in high-grade serous ovarian cancer (HGSOC), focusing on their ability to establish tumor-specific immune memory and effectively target autologous tumors. Through a combination of in silico, in vitro, and ex vivo approaches, we demonstrated that aNK cells, in contrast to conventional NK (cNK) cells, exhibit recall responses, specific cytotoxicity, and preferential infiltration into the tumor microenvironment (TME). Our data revealed that aNK cells interact with dendritic cells (DCs) within the TME via the HLA-E/NKG2C axis and CXCR2 signaling, contributing to their memory formation and tumor-targeting capabilities. These findings suggest that aNK cells could serve as potent agents in NK cell-based immunotherapies, particularly in solid tumors like HGSOC, where they resist immunosuppressive signals and maintain robust anti-tumor activity. This study provides new insights into the adaptive-like properties of aNK cells, underscoring their potential for advancing cancer immunotherapy strategies.