Lung Xenotransplantation: From the First Human Milestone to the Path of Clinical Translation

Lung transplantation remains the only curative treatment for end-stage lung diseases, yet a critical shortage of donor organs persists. Xenotransplantation using genetically modified pigs has emerged as a promising solution, with recent breakthroughs in cardiac and renal xenotransplantation demonstrating clinical feasibility. However, the unique anatomical and physiological characteristics of the lung pose distinct challenges that have delayed progress in pulmonary xenotransplantation. The first reported transplantation of a gene-edited pig lung into a brain-dead human recipient in 2025 represents a pivotal milestone, successfully preventing hyperacute rejection through triple-gene knockout combined with transgenic expression of human complement regulatory proteins and thrombomodulin. Yet the nine-day observation window revealed persistent challenges, including severe primary graft dysfunction and active antibody-mediated injury, highlighting that current genetic modifications remain inadequate for achieving long-term graft survival. This review systematically analyzes the layered immunological and physiological barriers to lung xenotransplantation and evaluates evolving intervention strategies that reflect a paradigm shift from passive molecular camouflage toward active immunological remodeling. Looking beyond biological barriers, successful clinical translation requires integrated solutions spanning scalable donor production systems, surgical adaptation, rigorous biosafety frameworks, ex vivo perfusion platforms, and non-invasive monitoring technologies. Ultimately, the success of lung xenotransplantation will depend not on isolated technological breakthroughs but on the systematic integration of genetic engineering, immune modulation, and translational infrastructure, offering new hope to patients with end-stage lung disease.