Abstract
Lungs remain one of the most difficult solid organs for xenotransplantation, owing to its delicate alveolar capillary barrier and intense crosstalk between innate immunity and coagulation system. Multi-gene-engineered donor pig organs combined with co-stimulation pathway blockade based immunosuppressive regimen have extended xenograft survival in preclinical models using non-human primates (NHP) from hours to weeks. Most recently, the first case of lung xenotransplantation into a brain-dead human recipient was reported, confirming technical feasibility without hyperacute rejection while revealing early inflammatory injury and progressive dysfunction. Key barriers include loss of vascular barrier function, dysregulated coagulation and platelet function driven by porcine-human molecular incompatibilities, and antibody-mediated injury. Preclinical data implicate innate immune activation such as natural killer cells and macrophages. Unlike kidney xenotransplantation, which has achieved stable long-term outcomes in NHPs, lungs require attention to immunogenicity against the "fourth antigen" in triple-knockout (TKO) donors that include the positive crossmatch created by the CMAH deletion when TKO organs are tested in NHP. Although consistent multi-month lung xenograft survival has not yet been achieved in preclinical models, the remaining barriers to clinical translation are being defined. This review delineates lung-specific xeno-immune mechanisms and advances aimed at their mitigation, providing insights necessary for future clinical translation.