Multiomic analyses in xenotransplantation: Hypothesis generation and the path toward precision diagnostics

Since the first successful allograft in 1954, the field has sought a method to monitor the delicate balance between immunosuppression and graft function. Over the last 20 years, multiomic approaches have provided increasingly detailed molecular characterization of the immunologic and physiological processes underlying graft injury. Xenotransplantation, now in its clinical infancy, has been a rapid adopter of multiomic analysis and benefited from lessons learned in allotransplantation. In our first edition of the AJT XenoPulse, we reviewed the progress made in living recipients and the clinical applications of xenotransplantation across cardiac, renal, and hepatic grafts. This second edition summarized the use of multiomics as a hypothesis-generating tool to guide next-generation donor-pig design and adjust immunosuppression, while exploring its contribution to the diagnosis of xenograft rejection. Across organs, emerging studies highlighted prominent innate immune responses and illustrated how tools developed in allotransplantation may need to be adapted to the cross-species setting. These findings are beginning to define a path toward integrated, xeno-specific diagnostics for clinical monitoring and trial design, although most signatures remain associative and will require analytical and clinical validation.