Multimodal precision diagnostics in clinical xenotransplantation.

Recent breakthroughs in pig-to-human xenotransplantation have successfully prevented hyperacute rejection of kidney, heart, liver and lung xenografts, marking a milestone long considered a critical barrier. However, these major advances also brought new challenges into focus, as immune-mediated graft injuries including antibody-mediated rejection, T cell-mediated rejection and innate immune activation have been observed in most xenotransplantation procedures to date. Detection and management of these injuries remain a critical bottleneck, as conventional histopathology and standard clinical monitoring lack the sensitivity required to identify subclinical injury early enough to guide timely intervention. This diagnostic gap underscores an urgent need for the development of advanced, multimodal precision diagnostic frameworks to enhance immune surveillance, which will be essential for standardizing clinical protocols and enabling pathogenesis-driven therapeutic intervention. This approach will inform both immunosuppressive regimens and future gene editing strategies aimed at engineering rejection-resistant porcine organs, ultimately prolonging graft survival. Broad adoption of such an integrative strategy will be essential to transition xenotransplantation from an experimental intervention into a safe, scalable and patient-centred clinical therapy. In this Review, we synthesize recent progress in xenotransplantation and position multimodal precision diagnostics as a pivotal strategy to address the remaining immunological and clinical barriers to widespread clinical implementation.