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While enhancement of PD\u2010L1 checkpoint molecules has exhibited potential in inhibiting T cell activity, its efficacy is often hindered by limited specificity and inadequate efficiency. Herein, a novel dual\u2010phase immune modulation strategy is developed in which CTLA4\u2010Ig and PD\u2010L1 provide distinct, non\u2010redundant inhibitory signals during the initial activation phase and the post\u2010activation phase of T cells. PD\u2010L1 is stably expressed on macrophages (sPD\u2010L1\u00a0M) through lentiviral transduction, allowing them to leverage their chemotactic and antigen\u2010presenting functions to target and deliver PD\u2010L1 to transplant rejection sites. Notably, sPD\u2010L1\u00a0M exhibited adaptive targeting capabilities, increasing their migration to grafts in response to heightened rejection. In an allograft skin model, the combined intravenous administration of sPD\u2010L1\u00a0M and subcutaneous administration of CTLA4\u2010Ig demonstrated synergistic efficacy, significantly suppressing alloreactive T cell activation, enhancing the recruitment of regulatory T cells (Tregs), downregulating pro\u2010inflammatory cytokines, and prolonging allograft survival compared to either treatment alone. This study presents a promising strategy to effectively suppress T cell activity and prevent allogeneic immune responses without systemic immunosuppression.<\/jats:p>","DOI":"10.1002\/adhm.202403591","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T02:32:08Z","timestamp":1745375528000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Macrophage\u2010Tased Dual\u2010Phase T Cell Immunomodulation to Combat Transplant Rejection"],"prefix":"10.1002","volume":"14","author":[{"given":"Wenyuan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Ultrasound Medicine Union Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 430022 China"},{"name":"Hubei Province Clinical Research Center for Medical Imaging  Wuhan 430022 China"},{"name":"Hubei Province Key Laboratory of Molecular Imaging  Wuhan 430022 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