Xenotransplantation: future frontiers and challenges

Purpose of review Recent advancements in genetic engineering have propelled the field of xenotransplantation from preclinical models to early compassionate use cases. As first-in-human clinical trials (FIHCTs) approach, we examine recent developments, ethical and regulatory challenges, immunological considerations, and the clinical infrastructure necessary for successful xenotransplantation trials. Recent findings Expanded access transplants of pig hearts, kidneys, and livers have identified key challenges. Heart xenotransplants revealed risks of antibody-mediated rejection and zoonotic infections, while kidney xenotransplants suggest that patient selection, rather than immune rejection, may have caused failures. While there has been a report of auxiliary liver transplantation conducted abroad, profound thrombocytopenia poses an obstacle. As FIHCTs draw near, critical clinical challenges include determining the optimal donor genetic constructs and immunosuppressive regimens. Enrollment criteria and patient selection pose additional complexity, alongside ethical concerns such as lifelong zoonosis monitoring. Only a limited number of centers have the expertise needed to conduct these complex trials. Summary Xenotransplantation holds great promise as a solution to organ shortages, but success in FIHCTs will require careful design, multidisciplinary collaboration, and strong infrastructure. Addressing immunologic, ethical, and patient selection challenges will be critical. With proper preparation, xenotransplantation could transform organ transplantation.