Porcine xenotransplantation in the clinical era: converging advances and unresolved barriers on the path to clinical translation - a narrative review

The persistent shortage of donor organs has renewed interest in porcine xenotransplantation as a scalable alternative to human allotransplantation. Advances in genome engineering and immunomodulation have accelerated the field from experimental proof-of-concept toward early clinical translation. This review summarizes recent progress in donor pig genetic modification, targeted immunosuppressive strategies, surgical implementation, and rejection surveillance. Multigene-edited pigs lacking major carbohydrate xenoantigens and expressing human complement, coagulation, and cytoprotective regulators have substantially reduced hyperacute and acute vascular rejection. In parallel, costimulation blockade targeting the CD40/CD154 pathway has enabled prolonged graft survival in non-human primates and supported the first pig-to-human heart and kidney transplants. Improvements in organ preservation, recipient selection, and molecular monitoring, including circulating graft-derived DNA and multi-omic profiling, have further strengthened translational readiness. Complementary porcine models, including pig-to-pig transplantation and vascularized composite tissue transplantation, provide valuable platforms for studying tolerance induction, surgical refinement, and long-term graft biology. Human-to-pig chimerism has also been explored as a potential strategy to promote immune tolerance and improve graft compatibility. Despite these advances, major barriers remain, including delayed antibody-mediated rejection, coagulation dysregulation, innate immune activation, infectious safety, and regulatory challenges. Porcine xenotransplantation has now entered an early clinical era, with durable immune control and long-term safety representing the next decisive milestones.