From bench to bedside: immune and genetic innovations driving the future of cardiac, renal, and hepatic xenotransplantation

Xenotransplantation, leveraging genetically engineered porcine donors, represents a promising solution to the global organ shortage crisis. Recent breakthroughs in genome editing have enabled the creation of pigs with multiple modifications, including knockout of key xenoantigens (GGTA1, CMAH, B4GALNT2) and insertion of human transgenes that regulate complement, coagulation, and innate immunity (e.g., hCD46, hCD55, hTBM, hCD47). Building on this genetic foundation, landmark clinical achievements have recently emerged. However, while the first porcine liver xenotransplants into human recipients demonstrated initial function, significant hurdles such as profound thrombocytopenia and coagulopathy—driven by factors like porcine vWF-human GPIb interactions and immune cell-mediated clearance—persist. Similarly, cardiac and renal xenotransplantation have seen milestones like the first pig-to-human heart transplants and extended kidney graft survival (up to 130 days) in a living recipient, yet delayed rejection and thrombotic microangiopathy remain critical challenges. Advanced strategies, including potent immunosuppression centered on anti-CD40 blockade, improved coagulation management (e.g., via hTFPI, hEPCR, hCD39), and emerging tolerance protocols, are actively being developed to overcome these barriers. This review synthesizes these pivotal 'bench-to-bedside' advancements, critically evaluating the current immunological and genetic innovations driving the progress of cardiac, renal, and hepatic xenotransplantation, and outlining the future directions necessary for successful clinical translation.