Substantially Altered Local and Systemic Immunity in Ischemia‐Free Versus Conventional Liver Transplantation

ABSTRACT Ischemia‐free liver transplant (IFLT) has been developed to reduce ischemia‐reperfusion injury (IRI). This study aims to investigate how this procedure impacts local and systemic immunity compared to conventional liver transplantation (CLT). Immunohistochemistry, immunofluorescence staining, single‐cell RNA sequencing (scRNA‐seq), and multiplex cytokine are used to illustrate distinct local and systemic immunity. In contrast to CLT, IFLT reduces neutrophil infiltration and neutrophil extracellular trap formation in grafts. By constructing an immune cell chimerism atlas, we reveal that IFLT reduces recipient‐derived monocyte infiltration by suppressing ANXA1‐FPR1 signaling through the STAT3‐HIF‐1α pathway, thereby attenuating inflammatory responses in graft monocytes. Additionally, IFLT confers graft protection by upregulating HMOX1 expression in monocytes and macrophages. Peripherally, IFLT significantly reduces the expression of MHC II molecules in circulating monocytes. Accordingly, CD8 + effector T cell composition, T helper 1 (Th1) and Th17 cytokine levels are reduced, while regulatory T cell (Treg) composition and Th2 cytokine levels are increased in IFLT versus CLT recipients. These results show that IFLT profoundly affects local and systemic immunity in liver transplantation. Recipient‐circulating monocytes might play a key role in the interaction between graft IRI and allograft rejection.