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ORIGINAL RESEARCH article

Front. Immunol.

Sec. Cancer Immunity and Immunotherapy

A comprehensive analysis of humanized mouse models for the study of cancer immunotherapies

Provisionally accepted
Philippe De La RocherePhilippe De La Rochere1Laure LoumagneLaure Loumagne2Melanie RathauxMelanie Rathaux1Marine DuboisMarine Dubois1Jordan DenizeauJordan Denizeau1Fariba NematiFariba Nemati1Sophie VielSophie Viel1Tamara SlavnicTamara Slavnic2Jayant ThatteJayant Thatte3Henry LiHenry Li3Xuesong OuyangXuesong Ouyang3Christine SedlikChristine Sedlik1Didier DecaudinDidier Decaudin1Georges AZARGeorges AZAR2Sukhvinder SidhuSukhvinder Sidhu2Eliane PiaggioEliane Piaggio1,4*
  • 1Institut Curie Centre de Recherche, Paris, France
  • 2Sanofi SA, Paris, France
  • 3Crown Bioscience Inc, San Diego, United States
  • 4Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France

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Abstract Humanized immune system (HIS) mouse models, generated by engrafting tumors and hematopoietic cells of human (Hu) origin into immunodeficient host mice, effectively recapitulate key aspects of the crosstalk between human immune cells and tumors. These models represent a valuable tool for the preclinical evaluation of immunotherapies. In this study, we provide a comprehensive comparison of two widely used HIS models: the Hu-CD34+ model, which engrafts Hu-hematopoietic cells derived from Hu-CD34+ hematopoietic stem cells (HSCs), and the Hu-PBMC model, which utilizes Hu-peripheral blood mononuclear cells (PBMCs). We assess the kinetics, quality and extent of immune cell engraftment, as well as the development of graft-versus-host disease (GVHD). Additionally, we investigate the impact of different immunodeficient host mouse strains on immune cell reconstitution in the Hu-CD34+ model. Both HIS models were engrafted with human tumors derived from either cell lines or patient-derived xenografts (PDX), revealing distinct immune-tumor interactions that influenced antitumor responses. Notably, tumor responses to T-cell-directed therapies, including anti-PD1 antibodies, IL-2-anti-IL-2 antibody complexes, and T-cell engagers, varied across these models. Our findings provide novel insights into the properties and limitations of HIS models, offering a critical resource for optimizing next-generation immuno-oncology strategies and guiding the design of future therapeutic interventions.

Keywords: Cancer, humanized mice, immune checkpoints, Immunodeficient mice, Immunotherapy

Received: 22 Oct 2025; Accepted: 16 Feb 2026.

Copyright: © 2026 De La Rochere, Loumagne, Rathaux, Dubois, Denizeau, Nemati, Viel, Slavnic, Thatte, Li, Ouyang, Sedlik, Decaudin, AZAR, Sidhu and Piaggio. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Eliane Piaggio

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Supplementary Material