Cardiac xenotransplantation: Progress, barriers, and pathways toward clinical translation

Cardiac xenotransplantation (CXTx) has emerged as a potentially transformative solution to the global shortage of donor organs, driven by recent breakthroughs in genome-editing technologies. This review provides a comprehensive overview of the field, tracing its evolution from early experimental barriers to the current stage of early clinical translation. We summarize the significant strides made in the development of genetically engineered donor pigs, in which multi-gene modifications have effectively overcome the obstacle of hyperacute rejection. Despite these advances, long-term graft survival remains limited by complex immunological and physiological challenges, including acute humoral xenograft rejection, cellular immune responses, and coagulation dysregulation. Furthermore, this review critically analyzes data from recent milestones, including studies in brain-dead decedent models and the first genetically modified pig-to-human heart transplants. These clinical endeavors have exposed critical unresolved issues, particularly antibody-mediated rejection and the biosafety risks associated with porcine viruses. In conclusion, we discuss the key pathways for future progress, emphasizing the urgent need for optimized immunosuppressive regimens, rigorous viral surveillance, and standardized preclinical protocols to establish CXTx as a safe and durable clinical reality.