Adaptive NK (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, 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 cells, exhibit recall responses, specific cytotoxicity, and preferential infiltration into the tumor microenvironment. Our data revealed that aNK cells interact with dendritic cells within the tumor microenvironment 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 such as high-grade serous ovarian cancer, in which they resist immunosuppressive signals and maintain robust antitumor activity. This study provides new insights into the adaptive-like properties of aNK cells, underscoring their potential for advancing cancer immunotherapy strategies.

Chemoradiotherapy (CRT) induces tumor cell death and remodeling of the tumor immune microenvironment. Adaptive natural killer (aNK) cells, initially characterized in chronic viral infection, are now recognized as important in solid tumors, contributing to antitumor immunity and immune memory. However, the dynamics of aNK cell response to CRT and the regulatory mechanisms behind their activation are not well understood. We analyzed single-cell RNA sequencing data from cervical cancer patients before CRT, after the first CRT fraction, and after the second fraction. We found that CRT markedly enriched aNK cells, with increased cytotoxicity and enhanced virus-defending programs. Among the differentially expressed genes, the transcription factor PRDM1 (PR/SET domain 1, also known as BLIMP-1:B lymphocyte-induced maturation protein 1) was consistently up-regulated in aNK cells after both rounds of CRT. To explore the potential role of PRDM1, we performed in silico perturbation analyses using scTenifoldKnk and CellOracle. These computational simulations predicted reduced effector-associated programs and perturbed metabolic networks following PRDM1 disruption in aNK cells. Moreover, PRDM1 perturbation altered inferred cellular trajectories, opposing the transcriptional shift toward an adaptive NK-associated state, suggesting that PRDM1 may contribute to maintenance of aNK-associated identity and functional features in the CRT-conditioned tumor microenvironment. These findings identify PRDM1 as a candidate regulator associated with aNK cell enrichment, activation-related remodeling, and trajectory-associated changes following CRT, providing insight into immune remodeling during CRT and highlighting PRDM1 as a promising regulatory candidate for future investigation in radiotherapy-induced antitumor immunity.

Adaptive NK (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, 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 cells, exhibit recall responses, specific cytotoxicity, and preferential infiltration into the tumor microenvironment. Our data revealed that aNK cells interact with dendritic cells within the tumor microenvironment 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 such as high-grade serous ovarian cancer, in which they resist immunosuppressive signals and maintain robust antitumor activity. This study provides new insights into the adaptive-like properties of aNK cells, underscoring their potential for advancing cancer immunotherapy strategies.

Immune cell-based immunotherapy has emerged as a promising strategy for both hematologic malignancies and solid tumors. The adaptive properties of T and B cells, namely, antigen specificity and long-term immune memory, form the foundation of approaches such as chimeric antigen receptor (CAR) T-cell therapy and tumor vaccines. In contrast, natural killer (NK) cells, traditionally classified as innate lymphocytes, have been appreciated primarily for their immediate cytotoxicity against tumor cells, but not for long-term memory-like responses. Recent evidence has revealed a subset of NK cells defined as adaptive NK cells (aNK) capable of developing adaptive features, particularly in response to cytomegalovirus (CMV) primarily, and more recently, to ovarian tumor-derived antigens. However, whether tumor-derived peptides can specifically induce NK cell memory, and the corresponding interaction patterns, remains largely unexplored. In this study, we employed a proteogenomic approach combining RNA sequencing (RNA-seq) with HLA-E immunoprecipitation to identify both canonical and non-canonical peptides presented by primary ovarian tumor cells. Among four tumor-derived neo-antigenic peptides, the 9-mer peptide APAPAPAPL demonstrated the strongest binding affinity to HLA-E and engagement with the NK receptors NKG2C/A. Functional in vitro assays confirmed that this peptide could induce memory-like NK cell responses, including antigen-specific recall activity and enhanced tumor cytotoxicity. Furthermore, structural modeling using AutoDock Vina and Rosetta Dock illustrated that peptides with similar binding capacity shared conserved interaction patterns and docking orientations. Together, this systemic study highlights a novel mechanism for inducing NK cell memory through tumor-derived neoantigens. It also paves the way for the development of NK cell-targeted cancer vaccines, representing a new direction in tumor immunotherapy beyond conventional T cell-centered strategies.