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Recent advances in high-dimensional technologies\u2014including single-cell sequencing, epigenomics, and metabolomics\u2014are driving a paradigm shift in transplant immunology from \u201cbroad suppression\u201d toward \u201cprecision modulation.\u201d This review systematically delineates the hierarchical network and regulatory mechanisms of the alloimmune response, with a focus on four pioneering therapeutic strategies: engineered cellular therapies, targeted biologics, local microenvironment remodeling, and metabolic\/epigenetic interventions. It further discusses the integration of novel biomarkers, high-dimensional technologies, and artificial intelligence to establish a precision medicine framework for personalized immune management. Finally, future directions and challenges\u2014including xenotransplantation, spatial multi-omics, and immune aging\u2014are explored, providing a conceptual and practical roadmap for the fundamental transition from systemic immunosuppression to precision modulation of the immune microenvironment.<\/jats:p>","DOI":"10.3389\/fcell.2026.1835561","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T05:44:23Z","timestamp":1779342263000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Transplantation immunology: paradigm shift from systemic suppression to microenvironment remodeling and precision modulation"],"prefix":"10.3389","volume":"14","author":[{"given":"Siqi","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Oncology, Guilin Hospital of the Second Xiangya Hospital, Central South University","place":["Guilin, Guangxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaochen","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Emergency and Critical Care Medicine, Chuzhou Integrated Traditional Chinese and Western Medicine Hospital","place":["Chuzhou, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengjie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University","place":["Hefei, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuting","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University","place":["Hefei, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beibei","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University","place":["Hefei, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Langlang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University","place":["Hefei, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University","place":["Hefei, Anhui, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"13239","DOI":"10.3389\/ti.2024.13239","article-title":"Perspective for donor-derived cell-free DNA in antibody-mediated rejection after kidney transplantation: defining context of use and clinical implications","volume":"37","author":"Akifova","year":"2024","journal-title":"Transpl. 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