Stepwise Evolution of Immunodeficient Mouse Models: Focus on NCG Strains and Their Applications in Humanized Immune System Research

Immunodeficient and humanized mouse models have become essential tools for investigating human immunity, disease pathogenesis, and therapeutic evaluation. This review summarizes the stepwise evolution of these platforms, from nude and SCID mice to advanced NOD/SCID/Il2rgnull strains (NCG, NSG, or NOG), and highlights how progressive removal of murine immune barriers has improved human cell engraftment and experimental utility. Major humanized immune system (HIS) approaches, including Hu-PBMC/PBL, Hu-HSC, and Hu-BLT models, are compared with respect to engraftment kinetics, immune composition, graft-versus-host disease, and suitability for distinct research applications. Particular emphasis is placed on next-generation engineered strains that enhance specific human immune compartments, including cytokine-humanized models for myeloid, dendritic cell, natural killer cell, and neutrophil reconstitution; TSLP-based models that restore secondary lymphoid organogenesis and improve adaptive immune responses; and advanced HLA-humanized models. These advances have substantially expanded the value of humanized mice in studies of autoimmune disease, cancer immunotherapy, and vaccine evaluation. Nevertheless, no single model fully reproduces the complexity of the human immune system, and major limitations remain, including incomplete stromal humanization, restricted HLA diversity, and inter-model variability. Continued refinement will be critical for improving translational relevance and predictive power in vaccine and immunology research.