Advancements and Challenges in Mouse Models for NK Cell-Based Cancer Immunotherapy

NK cells are key components of the innate immune system, capable of recognizing and eliminating tumor or virus-infected cells and able to modulate both innate and adaptive immune responses. This makes NK cells attractive candidates for cancer immunotherapy, through passive approaches such as adoptive NK cell transfer, or active approaches aimed at enhancing endogenous NK cell activity in vivo. Promising results have emerged from preclinical studies and early-phase clinical trials. Nevertheless, the therapeutic efficacy of NK cell-based approaches is often limited by several factors, such as the poor NK cell persistence in vivo, the inefficient tumor infiltration, and the immunosuppressive milieu typical of the tumor microenvironment. The preclinical development of NK cell-based therapies relies largely on animal models. Humanized mouse models have evolved from early immunodeficient strains to more advanced systems incorporating human cytokines, which more effectively support NK cell development, maturation, and function. These models have substantially improved our understanding of human NK cell biology and enabled the evaluation of novel therapeutic strategies. However, further optimization is still required to better recapitulate the tissue-specific heterogeneity of human NK cells and their conditioning by the tumor microenvironment. In this review, we provide an overview of recent advances in the generation of humanized mouse models for NK cell-based cancer immunotherapy, discussing their advantages and limitations and highlighting how emerging technologies may contribute to the development of more predictive preclinical platforms.