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

## TL;DR

This review discusses the development of humanized mouse models to better study and improve NK cell-based cancer immunotherapies.

## Contribution

The paper highlights recent progress and remaining challenges in creating more accurate preclinical models for human NK cell research.

## Key findings

- Humanized mouse models have improved the understanding of human NK cell biology and therapeutic evaluation.
- Current models still struggle to fully replicate human NK cell heterogeneity and tumor microenvironment interactions.
- Emerging technologies may help create more predictive preclinical platforms for NK cell-based therapies.

## Abstract

Natural killer (NK) cells are innate immune cells with a critical role in the recognition and elimination of malignant cells and have therefore attracted considerable interest as targets for cancer immunotherapy. Despite encouraging results in experimental settings, the clinical performance of NK cell-based approaches can be improved. One of the major limitations is the inability of conventional animal models to accurately reproduce human NK cell development, persistence, and functional regulation within the tumor microenvironment. This review discusses the need for more advanced preclinical models and examines recent progress in the development of humanized mouse systems that more faithfully recapitulate key traits of human NK cells. By outlining both the advantages and the remaining limitations of these models, this work aims to inform the research community and support the design of more predictive preclinical studies, ultimately facilitating the translation of NK cell-based therapies into effective cancer treatments.

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.