Advancing humanized mouse models for translational immunology and immunotherapy: Benchmarking, standardization, and next-generation design principles

Humanized mouse models have become essential platforms for investigating human immune development, function, and disease in vivo. By engrafting immunodeficient mice with human hematopoietic stem cells, peripheral blood mononuclear cells, immune tissues, or patient-derived tumors, these models provide experimentally tractable systems in which human immune responses can be studied under physiological and pathological conditions. Recent advances in host genetics, human cytokine expression, HLA matching, tissue engineering, and multi-omics analysis have improved the development and function of human lymphoid and myeloid compartments. These innovations are expanding the use of humanized mice beyond infectious disease research into cancer immunology, autoimmunity, allergy, transplantation, reproductive immunology, and the preclinical evaluation of immune-modulating therapies. However, variation in host strain, donor source, engraftment, and assay endpoints can limit reproducibility and cross-study comparison. Progress therefore depends on rigorous benchmarking, quality control, and immunological design principles that define when a model is fit for a specific translational purpose.

This Research Topic aims to advance the engineering, comparative evaluation, and immunological design of humanized mouse models, with model benchmarking, reproducibility, quality-control standards, and fit-for-purpose selection as its central themes. A central challenge is that no single model fully reproduces the complexity of the human immune system. Incomplete myeloid, NK-cell, B-cell, and tissue-resident immune development; donor-to-donor variability; xenogeneic graft-versus-host disease; species-specific cytokine incompatibility; and limited human lymphoid architecture can all affect experimental interpretation. We therefore seek studies that benchmark models using defined performance criteria, report donor and host variables transparently, establish quality-control measures for immune reconstitution and function, and guide fit-for-purpose model selection. Next-generation models should address defined limitations of existing systems. Validation may include comparison with patient samples, clinical responses, or complementary human in vitro systems. Disease- or therapy-specific studies, including those of immunotherapies and vaccines, should provide substantive methodological development, comparative evaluation, or biological validation of the model itself. Future humanized mouse models will likely benefit from integrating multiple immunoregulatory modules identified through study design and experimental findings, including mechanisms of self–non-self recognition, cross-species immune coexistence, and immune tolerance, to construct rational design principles derived from human physiology.

We welcome Original Research, Methods, Reviews, Mini Reviews, Perspectives, and Brief Research Reports addressing: benchmarking of HSC-, PBMC-, BLT-, and tissue-based models; standardized reporting and quality-control workflows; reproducibility across donors, host strains, facilities, and batches; and fit-for-purpose model selection. Additional areas include next-generation host strains and human cytokine or HLA knock-in models; development of lymphoid, myeloid, and tissue-resident immune compartments; tumor and patient-derived xenograft models; infection, autoimmunity, allergy, transplantation, and reproductive immunology; immunotherapies, vaccines, immune-related adverse events, and xenogeneic GVHD; and validation using patient samples, complementary human in vitro systems, spatial, single-cell, or multi-omics analyses. Disease- or therapy-specific submissions must demonstrate substantive model development, benchmarking, or biological validation rather than using a humanized mouse solely as an application platform. Comparative and reproducibility studies, including work defining model limitations, are particularly encouraged.