Extracorporeal Photopheresis in Heart Transplantation: From Salvage Therapy to Immunosuppression-Sparing Strategy.

Heart transplantation remains the definitive therapy for end-stage heart failure, yet graft survival continues to be limited by acute and chronic rejection and the cumulative toxicity of lifelong immunosuppression. Extracorporeal photopheresis (ECP), an immunomodulatory therapy with established efficacy in graft-versus-host disease and lung transplantation, has been investigated for more than 3 decades as an adjunctive therapy in heart transplantation. While prior reviews have summarized historical outcomes, the role of ECP in contemporary transplant practice remains incompletely defined. This state-of-the-art review examines the immunologic basis, clinical evidence, and evolving applications of ECP in heart transplant recipients, with particular focus on rejection prophylaxis, acute cellular rejection, recurrent rejection, and antibody-mediated processes. We contextualize existing evidence within modern immunosuppressive regimens and emerging noninvasive rejection surveillance tools, including donor-specific antibodies and molecular biomarkers. Beyond its role as salvage therapy, accumulating evidence suggests that ECP may function as an immunosuppression-sparing strategy, particularly in high-risk patients with recurrent rejection, infection vulnerability, or intolerance to intensified immunosuppression. We highlight unresolved knowledge gaps, propose patient selection frameworks, and identify future research directions necessary to define the role of ECP in modern heart transplantation. Overall, ECP appears to be a safe and underutilized adjunct with potential to reduce rejection burden while mitigating the long-term consequences of immunosuppression.