INTRODUCTION Recent clinical cases involving the transplantation of genetically modified pig organs into living patients have highlighted the remarkable progress in the field of xenotransplantation over the past few years. The World Transplant Congress (WTC), held in San Francisco from September 2–6, 2025, stood out as the pinnacle event in organ transplantation (Congress abstracts, see: https://wtc2025.org). It was jointly organized by the American Society of Transplant Surgeons, the American Society of Transplantation, and The Transplantation Society. The congress served as a global platform for experts to share research, discuss advancements, and address ongoing challenges in transplantation. At the forefront of the meeting were landmark xenotransplantation cases, including presentations on the groundbreaking outcomes of the first successful transplants of multitransgenic pig hearts and kidneys into living recipients. The event also showcased how major advances across various transplantation platforms can be integrated for mutually beneficial outcomes such as the latest combination of liver xenotransplantation with machine perfusion, used as a platform for extracorporeal liver support. All abstracts accepted for presentation on xenotransplantation at the WTC 2025 were published in the American Journal of Transplantation and can be uploaded in PDF from the following web link; https://www.sciencedirect.com/search?qs=xenotransplant&pub=AmericanJournalofTransplantation&cid=782964&years=2025&articleTypes=ABS&show=50. Other significant areas of interest were the clinical application of genetically modified pig organs, their associated immunological challenges, overall ethical considerations, and future directions of the field in relation to regulation, ethics, and patient selection. Figure 1 highlights the developments that have occurred over the past decade. In particular, the successful transplantation of gene-edited pig hearts, kidneys, and livers into humans, where xenotransplantation has transitioned from experimental to clinical practice. Along with the main meeting a premeeting workshop (WS04: Xenotransplantation—Regulatory Challenges and Clinical Implementation) on the regulatory landscape for xenotransplantation was well attended. There the emphasis focused on the importance of regulatory frameworks, public engagement, and international collaboration to ensure safe and ethical implementation of xenotransplantation on a world stage. It also demonstrated that the global shortage of donor organs continues to drive innovation in transplantation, where xenotransplantation has emerged as a promising solution.FIGURE 1.: Is a pictorial representation of xenotransplantation milestones as presented 20, at the WTC meeting. It includes the latest advances in the field including the development of transgenic pigs, targeted immunosuppression, new technology platforms, ethics and governance documents and highlights of key recent clinical xenotransplants in both decedent and living recipients.GENETIC ENGINEERING AND DONOR PIGS Advances in gene editing technologies, particularly CRISPR-Cas9, have enabled the creation of pigs with multiple genetic modifications to reduce immunogenicity and improve compatibility with human recipients. Presentations by Alfred (Jo) Tector and others highlighted the development of triple knockout (TKO) pigs lacking GGTA1, CMAH, and B4GALNT2 genes, combined with the insertion of human transgenes such as CD46, thrombomodulin, and CD55 (see: https://wtc2025.org). These modifications developed to prevent hyperacute rejection and improve graft survival based on protection against both the humoral and cellular immune systems. The use of such multigene-edited pigs in the recent clinical trial undertaken at the Massachusetts General Hospital (MGH) has demonstrated extraordinary long-term outcomes with functional graft survival for several patients, one being over 9 mo in a recipient despite earlier patient issues.1 CLINICAL TRIALS AND OUTCOMES WTC 2025 featured updates from ongoing clinical trials of kidney, cardiac, and hepatic xenotransplantation. Robert Montgomery reported on behalf of the New York University Langone Health team, describing outcomes of one of the first surviving recipients of a pig kidney xenograft, with over 60 d of function and, most importantly in these landmark cases, no signs of hyperacute rejection.2 Leonardo Riella presented data on behalf of the MGH team regarding the recipients enrolled in the current ongoing clinical trial at their institution. The initial recipient a 62-y-old man with long-standing diabetes and renal failure having lost most access for hemodialysis. He received a gene-edited porcine kidney with 69 genomic edits, including deletion of 3 glycan antigens and insertion of 7 human transgenes. The xenograft worked immediately reducing the patient’s creatinine levels to the normal range. Despite sustained normal kidney function, this patient died from unexpected cardiac causes on day 52. This patient had underlying severe coronary artery disease and ventricular scarring, but most importantly, the genetically modified kidney xenograft did not show signs of rejection.1 Dr Riella presented the 2 new recipients of the currently approved MGH trial with both recipients demonstrating stable renal function and evidence of controlled alloimmune activation under CD40 costimulatory pathway blockade, indicating effective immunosuppression. These patients have demonstrated normal creatinine clearance and absence of thrombotic microangiopathy, with both patients having extended graft survival, one >9 mo and the other almost 4 mo at the time of writing this article (see https://wtc2025.org). Originally leading the field with the first cardiac xenotransplants into live patients, Muhammad Mohuiddin described the outcomes of the University of Maryland Medical Center team efforts using GTKO/hCD55 pigs and their team’s novel immunosuppressive regimen.3 The key findings detailed were the significant outcomes of the 2 patients that had received genetically engineered pig hearts targeted to improve graft survival and using a CD40/CD154 blockade immunosuppressive regimen. Although complement activation was effectively attenuated with the CD40/CD154 blockade regimen, persistent challenges remained in managing coagulation dysregulation and achieving endothelial compatibility, potentially underscoring the need for further optimization of the donor xenograft. The great success of these landmark cases has demonstrated the clear importance and utility of the decades of the underlying nonhuman primate research that lead the University of Maryland Medical Center team’s success. The initial recipient surviving longer than any live recipient of a genetically engineered pig heart. The findings of these patients demonstrated that hyperacute xenograft rejection was avoided. They were able to identify potential mediators of endothelial injury, first, the widespread endothelial injury indicated antibody-mediated rejection. Second, that intravenous immunoglobulin bound strongly to donor endothelium, possibly causing immune activation. Finally, reactivation and replication of latent porcine cytomegalovirus/porcine roseolovirus in the xenograft possibly initiated a damaging inflammatory response. The findings point to specific measures to improve xenotransplant outcomes in the future and the need for further evaluation.3 Abraham Shaked provided experiences from initial clinical trials of extracorporeal liver xenotransplantation from the early 1990s, which supported patients as a bridge to allotransplantation. He also discussed recent studies that combine several emerging technologies coming together to create an impressive ex vivo support devices for patients suffering from acute-on-chronic liver failure. He presented the work of the University of Pennsylvania team’s use of a genetically modified pig liver (EGEN-5784) on a machine perfusion device (OrganOx metra) and exchange pump as an extracorporeal platform to provide perfusion to and from a series of 4 brain-dead patients. The successful outcomes demonstrated up to 110 h of hepatic support and normal physiological outcomes in these studies (see https://wtc2025.org). Another landmark presentation was from the group at the Xijing Hospital, Xi’an, China, of the case of a heterotopic auxiliary liver xenotransplant where a 6-gene-edited pig liver was transplanted into a brain-dead recipient. Graft function, hemodynamics, and immune and inflammatory responses of the recipient were monitored over a 10-d study period. Blood flow velocity in the porcine hepatic artery and portal and hepatic veins remained stable throughout the study. Histology demonstrated that genetically modified porcine liver functioned normally with no signs of hyperacute or cellular rejection. There were no significant perioperative changes in immunoglobulin G or M levels. The xenograft remained functional for the 10-d study period.4 IMMUNOLOGICAL INSIGHTS Sessions including IVS049 and OA02 explored the immune mechanisms underlying xenograft rejection. Paige Porrett highlighted the role of innate immune cells, particularly macrophages and natural killer cells, in early xenograft rejection. Brendan Keating and Steven Kim presented data from spatial transcriptomics and single-cell RNA sequencing, revealing dynamic immune cell infiltration and endothelial activation of xenografts. Along with an overview on the “The Right Immunosuppression” Jo Tector provided insights on the development of and need for targeted immunosuppressive strategies, including CD40/CD154 blockade and regulatory T-cell therapies focused on long-term xenograft survival and minimal impact to patients (see https://wtc2025.org). REGULATORY AND ETHICAL CONSIDERATIONS The regulatory landscape for xenotransplantation was a central focus of discussion, reflecting the growing momentum and complexity of translating cross-species organ transplantation into clinical practice. Vijay Kumar provided a detailed overview of the US Food and Drug Administration’s requirements for Investigational New Drug applications, highlighting the rigorous preclinical and clinical data needed to ensure safety, efficacy, and ethical compliance. Laura Kimberly addressed critical ethical considerations, including the importance of robust informed consent processes and the humane treatment of source animals to be used in xenotransplantation programs (see https://wtc2025.org). Wayne Hawthorne stressed the urgent need for harmonized global guidelines and transparent communication with patients and the public, highlighting that responsible, ethical progress in xenotransplantation depends on international collaboration as clinical trials expand (see https://wtc2025.org). This aligns with the ongoing efforts of the International Xenotransplantation Association (IXA), which has taken a leading role in shaping the regulatory framework for xenotransplantation. The IXA, in partnership with the World Health Organization and TTS, has developed a series of position papers and white papers that outline best practices for clinical trials,5 infectious disease surveillance,6 ethical standards,7 increased surveillance with a need for internationally recognized registry8 and a focus on patient and animal welfare.9 These documents serve as foundational tools for national regulatory authorities and are designed to facilitate international consistency in xenotransplantation oversight. They address application-specific milestones for different organ types, ensuring that each xenotransplantation product meets stringent criteria before entering human trials. The IXA’s work has been instrumental in promoting standardization, legislative harmonization, and public engagement, all of which are essential for the responsible deployment of xenotransplantation technologies. FUTURE DIRECTIONS The WTC highlighted major advances in xenotransplantation, now nearing clinical trials. Key priorities remain to further refine donor pig genetics, improve immunosuppression, and explore tolerance strategies such as mixed chimerism and regulatory T-cell therapy. Experts favor nonhuman primate models over decedent models because of better stability and monitoring potential. Multiomic profiling and AI will support personalized immunosuppression and rejection monitoring. International collaboration remains essential to align regulatory frameworks and update the xenotransplantation registry, as emphasized by the IXA council, which also advocates for trials in healthier patients with extended follow-up.10 In light of recent advancements, we are rapidly approaching a future envisioned by one of the modern era pioneers of xenotransplantation, David Cooper, who concluded his lecture at WTC with the quote: “One day, organ transplantation from deceased human donors will be of historic interest only.” Moreover, with continued progress in gene editing technologies, it is anticipated that immunosuppressive therapy may eventually become obsolete. These transformative developments signal a paradigm shift in transplantation medicine, with xenotransplantation poised to redefine the boundaries of clinical practice and the ability to transplant many more patients at a far more rapid pace. KEY LEARNING POINTS 1. Transition of xenotransplantation from experimental to clinical therapy Landmark cases of genetically modified pig heart and kidney transplants into living human recipients were presented, demonstrating functional graft survival and absence of hyperacute rejection. These landmark cases are a pivotal shift in xenotransplantation with translation from preclinical research to clinical application. 2. Gene editing technologies enable enhanced compatibility The use of CRISPR-Cas9 to create multitransgenic pigs (eg, TKO pigs with human transgenes such as CD46, CD55, and thrombomodulin) has prevented HAR and significantly reduced immunogenicity. These modifications have led to prolonged graft survival in live human patients, with 1 TG porcine kidney xenograft functioning in a patient for >9 mo. 3. Immunosuppressive strategies are evolving Novel regimens such as CD40/CD154 blockade have shown promise in preventing complement activation and cellular rejection. However, challenges remain in managing coagulation and endothelial compatibility, highlighting the need for further refinement of both donor genetics and recipient immunosuppression. Along with continued research in preclinical models. 4. Extracorporeal liver xenotransplantation offers bridging support Combining genetically modified pig livers with novel machine perfusion platforms has enabled up to 110 h of hepatic support in a series of brain-dead patients. This would suggest that it is a viable bridge-to-transplant strategy for acute liver failure and a new avenue for ex vivo organ support. A clinical trial application has been approved to proceed in live patients. 5. Global collaboration and regulatory frameworks are essential The WTC premeeting workshop emphasized the importance of ongoing international cooperation, public engagement, and robust regulatory oversight to ensure the ethical and safe implementation of xenotransplantation. The IXA in combination with the TTS and World Health Organization are ensuring these frameworks are updated as the xenotransplantation field moves toward broader clinical adoption. ACKNOWLEDGMENTS The author acknowledges Erin Fuller for generation of Figure 1, which was created in BioRender, and Thanh Le for referencing.
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