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Advances in genetic engineering, particularly the targeted knock\u2010in of human cytokines, have enabled robust development and function of human immune cells in these models. Recent breakthroughs\u2014including the directed differentiation of human pluripotent stem cells into thymic epithelial cells and the efficient expansion of hematopoietic stem cells\u2014have alleviated the constraint of scarce human tissue sources. Furthermore, the reconstruction of lymph node structures and successful engraftment of solid organ tissues have significantly improved the efficiency and physiological relevance of human immune system reconstitution. These models now provide a unique platform for in\u00a0vivo studies in cancer immunotherapy, infectious diseases, regenerative medicine, and autoimmune disorders under near\u2010physiological conditions. Beyond rodents, substantial progress in humanized large animals, such as pigs, offers promising avenues for large\u2010scale immune system reconstruction and mass production of immunotherapeutic cells. This review presents a comprehensive overview of the development, optimization, and expanding applications of humanized animal models, highlighting their transformative role in advancing translational medicine.<\/jats:p>","DOI":"10.1002\/ame2.70228","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T04:02:49Z","timestamp":1780632169000},"page":"914-931","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Recent advances in the construction of humanized animal models and applications in translational medicine"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9406-880X","authenticated-orcid":false,"given":"Yanan","family":"Lyu","sequence":"first","affiliation":[{"name":"Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, and National\u2010Local Joint Engineering Laboratory of Animal Models for Human Diseases The First Hospital of Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong\u2010Guang","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, and National\u2010Local Joint Engineering Laboratory of Animal Models for Human Diseases The First Hospital of Jilin University  Changchun China"},{"name":"International Center of Future Science Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8310-4224","authenticated-orcid":false,"given":"Zheng","family":"Hu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, and National\u2010Local Joint Engineering Laboratory of Animal Models for Human Diseases The First Hospital of Jilin University  Changchun 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