Document resource
Background Natural Killer (NK) cells play a pivotal role in innate immune responses and antitumor immunity through cytolytic activity and immunomodulatory cytokine production, making them key targets for cancer immunotherapy and therapeutic antibody evaluation, particularly in Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC). Two different cytokines, IL-2 and IL-15, are critical to NK cell development and function.Methods To advance NK cell research, we developed two next-generation immunodeficient NCG mouse models: NCG-hIL2 and NCG-hIL15, engineered to express human IL-2 and IL-15, respectively. These models enable robust human NK cell reconstitution upon engraftment with peripheral blood mononuclear cells (PBMCs) or hematopoietic stem cells (HSCs).Results In this study, we demonstrate that the NCG-hIL2 model exhibits superior capacity for human NK cell reconstitution, confirming the essential role of IL-2 signaling in NK cell development and maintenance. Importantly, the NCG-hIL15 model supports robust co-engraftment of both human T and NK cells, establishing its unique value for comprehensive evaluation of immunotherapeutic agents targeting both adaptive and innate immune responses.We further validated the NCG-hIL2, NCG-hIL15 models for preclinical immunotherapy assessment, demonstrating NCG-hIL2 model’s utility in evaluating ADCC antibodies like Trastuzumab, Margetuximab, Rituximab and Blinatumomab. Collectively, the NCG-hIL2 and NCG-hIL15 models offer powerful tools for investigating NK cell biology, cytokine-driven development, and immunotherapy evaluation.Conclusions By leveraging humanized cytokine signaling, these systems bridge translational gaps in preclinical research, enabling refined assessment of NK cell-targeted therapies.