Humanized Immune Mouse Models: Emerging Applications for Cancer Immunotherapy

The preclinical efficacy of tumor immunotherapy is often evaluated using mouse models. However, due to species differences, conventional normal or nude mouse models cannot fully replicate the human immune response, resulting in many mouse-based research findings being inconsistent with the outcomes of clinical trials. Recently, the development of Severe Combined Immunodeficient (SCID) mice has paved the way for the reconstitution of a human CD45⁺ immune cell population exceeding 25% within the host, greatly assisting researchers in addressing these challenges. By engrafting human CD34⁺ hematopoietic cells, peripheral blood mononuclear cells, organoids, or fetal tissues into SCID mice-including various non-obese diabetic Prkdc^-/-IL2rg^-/- mice (commonly referred to as NSG, NCG, or NXG) and NSG mice expressing human cytokines- these models not only confer human immune functionality for the investigation of human innate immunity and specific viral infections but also facilitate the development and survival of human cancer cell-derived or patient-derived xenografts for immuno-oncology research. Despite the presence of graft-versus-host disease and a short experimental duration, this approach facilitates the investigation of tumor growth mechanisms within a human tumor immune microenvironment. It also enables the evaluation of the efficacy of human-specific immunotherapies, including CART and CAR-NK therapies, immune checkpoint inhibitors, and combination therapies, along with their underlying mechanisms. This article summarizes the latest research advancements and existing challenges related to SCID mouse models and humanized immune system mouse models, as well as their applications and obstacles in immuno-oncology research.