Xenotransplantation Literature Update: January–June 2025

ABSTRACT

From January to June 2025, the field of xenotransplantation progressed rapidly toward clinical translation, with landmark compassionate‐use cases, peer‐reviewed reports of porcine kidney, heart, and liver transplants in humans, and the release of authoritative international guidelines. This literature update summarizes key developments across clinical trials, immunological insights, donor engineering, preservation strategies, infection control, and ethical frameworks, highlighting a growing consensus on the scientific and regulatory roadmap for safe, effective, and equitable xenotransplantation.

1. Introduction

Between January and May 2025, the field of xenotransplantation made outstanding progress in clinical translation, marked by several compassionate‐use cases of genetically engineered pig kidney xenotransplantation and the publication of the analysis and lessons learned from the first clinical case. This period also saw continued progress in immunomodulation and donor engineering. Building on decades of preclinical work, pig‐to‐human kidney xenotransplantation has now entered the clinical trial arena, supported by robust mechanistic studies and multi‐institutional, multicompanies’ collaborations. At the same time, ethical, regulatory, and public engagement efforts have intensified to ensure responsible translation of this emerging science.

A recent systematic bibliometric analysis quantified this expanding global interest in xenotransplantation, identifying a renewed surge in publication activity during the early 2020s–particularly in immune mechanisms, gene editing, and organ‐specific models–while also underscoring persistent gaps in original clinical data and limited penetration into general medical literature [1]. Our review summarizes key peer‐reviewed publications from this timeframe, highlighting developments that continue to shape the future of xenotransplantation across scientific, clinical, and ethical domains.

2. Position Papers on Xenotransplantation

A recent series of landmark position papers published in Transplantation by the International Xenotransplantation Association (IXA) provides a comprehensive and authoritative foundation for the field's clinical advancement. The first paper, by Hawthorne et al., outlines the historical trajectory and regulatory framework that have enabled recent clinical breakthroughs, highlighting innovations in genetic engineering, immunosuppression, and ethical oversight [2]. Meier et al. focus on kidney xenotransplantation, summarizing key findings from nonhuman primate and human decedent studies, and offering concrete recommendations for clinical trials, including pig genetics, immunosuppression, and stringent patient selection criteria [3]. Fishman et al. address the unique infectious risks of xenotransplantation, such as PERV and PCMV, and emphasize the need for rigorous donor screening, recipient surveillance, and use of advanced diagnostic tools like metagenomic sequencing [4]. Reporting on international efforts, Hu et al. present the International Human Xenotransplantation Inventory, a growing global registry that has cataloged over 50 xenotransplant procedures to date, and advocate for expanding and integrating this resource to ensure transparency, data harmonization, and international collaboration [5]. Together, these position papers serve as a critical guide for clinicians, researchers, and policymakers, supporting the responsible and evidence‐based clinical translation of xenotransplantation.

3. Studies in Human

Building on the clinical milestones achieved in 2024, the first half of 2025 saw the peer‐reviewed publication of these studies. Kawai et al. published their findings on the life‐supporting xenotransplantation of a 69 gene‐edited porcine kidney into a 62‐year‐old living patient with end‐stage renal disease. The graft functioned for nearly 2 months until the patient unexpectedly died of cardiac related cause. Surprisingly, an episode of early T‐cell–mediated rejection was noted and reversed with thymoglobulin, highlighting unique immunologic challenges of clinical xenotransplantation [6]. Notably, the graft was free of significant rejection at the 2‐month mark.

In a parallel effort, the Maryland group reported their outcomes from the second 10 gene‐edited porcine heart into a living human recipient [7]. The heart xenograft had excellent function initially; however, on postoperative day (POD) 13, the endomyocardial biopsy retrospectively showed prominent capillary antibody and complement staining (IgG, IgM, C3d, and C4d) concerning for antibody‐mediated rejection (AMR). POD 29 was marked by hemodynamic decompensation and despite maximal immunosuppression including therapeutic plasma exchange, eculizumab (complement inhibitor), Berinert (c1 esterase inhibitor), and carfilzomib (proteasome inhibitor), on top of heavy induction and maintenance therapy including tegoprubart (costimulation blockade), the patient was placed on ECMO on day 31 and passed away on day 40. The transfusion of blood products and possible passive transfusion of xenoreactive antibodies was pointed out as a potential contributor of severe AMR. Despite the disappointment by this outcome, each case provides a significant volume of knowledge. Important to note in this particular case is that the patient experienced a ventricular fibrillation arrest 12 h prior to the xenotransplant, highlighting both the severity of illness in compassionate‐use cases and the urgent need for alternative treatments.

Finally, the first half of 2025 saw the report of a gene‐edited porcine liver transplanted as an auxiliary transplant in a brain‐dead patient [8]. The authors describe the use of a six‐gene–edited pig liver heterotopically transplanted in an effort to provide temporary metabolic and synthetic support, and ultimately serve as a bridge to possible allotransplantation. The xenograft remained functional for 10 days, producing bile and porcine albumin, with stable hepatic blood flow. Although the authors report no signs of rejection, C3d, C4d, and C5b‐9 deposition were observed in the explant, along with clear IgM and IgG staining, suggestive of early humoral activation. Immunosuppression included antithymocyte globulin, rituximab, etanercept, eculizumab, and standard maintenance therapy with tacrolimus, mycophenolate mofetil, and steroids. The short study duration, nonphysiological implantation, and use of a brain‐dead recipient limit broader clinical conclusions.

4. Recipient Immune Response

Despite the advances in human clinical applications, much remains to be elucidated regarding the immune mechanisms that drive xenograft rejection. Several studies highlighted the central role of innate and adaptive immunity in early xenograft injury. Parallel work showed that porcine kidney xenografts elicit strong activation of cytotoxic T lymphocytes [9] and NK [10] cells in primate and human models, reinforcing the need to target both arms of the immune response in xenotransplantation settings.

To further dissect these responses, multiomics profiling of cardiac xenografts in humans and primates has provided critical insight into rejection pathways. Specifically, activation of NF‐κB was identified as a central driver of graft failure in pig‐to‐NHP heart models, associated with increased myocardial inflammation and antibody deposition. Inhibition of NF‐κB extended graft survival and reduced immune cell infiltration, supporting its role as a promising immunomodulatory target [11]. Likewise, proteomic analyses of cardiac xenografts revealed distinct inflammatory signatures associated with graft dysfunction, further guiding the rational design of immunosuppressive regimens [12].

Genetic engineering continues to shape immune evasion strategies, for example, with the production of pigs with 6 gene modifications [13]. In this study, the authors generated six‐gene–edited Bama miniature pigs by knocking out GGTA1, CMAH, and β4GalNT2 and inserting hCD46, hCD55, and hTHBD, demonstrating normal physiology and organ function, thereby providing a promising model for xenotransplantation.

5. Safer Xenotransplantation: Recipient Selection, Donor Screening, Blood Product Utilization

TThorough donor–recipient histocompatibility evaluation is critical for successful xenotransplantation outcomes. Complement‐dependent cytotoxicity assays, widely used to assess potential xenograft outcomes, were recently evaluated for improvement by substituting human complement for rabbit complement [14]. The authors demonstrated that human complement more accurately revealed the protective effects of human complement regulatory proteins (such as hCD55) expressed on gene‐edited pig PBMCs, showing markedly reduced cytotoxicity compared to rabbit complement assays. This suggests that employing human complement in CDC assays may better predict the in vivo behavior of xenografts in human recipients.

Another often‐overlooked concern is blood product compatibility with the donor xenograft. Blood products (e.g., packed red blood cells, platelets, or fresh frozen plasma) are commonly utilized in allotransplantation–either to address rejection in the case of intravenous immunoglobulin (IVIg) or supplement anemia, thrombocytopenia, or deficiency in coagulation factors. Given the potential mechanism for blood products to serve as a source of passive antibody transfusion in the second xenoheart case, this issue is of significant relevance. Specifically, IVIg was revisited, with a call to action to optimize its timing and dosage in the context of xeno‐specific immune responses [15].

In situations where a blood product is required, one approach is to screen and clean the products for safe transfusion. However, this process may be costly and labor‐intensive as anti‐pig xenoreactive antibodies, including anti‐non‐α‐Gal antibodies, can be detected in multiple blood products [16]. The best approach to avoid the passive transfer of anti‐pig antibodies during transfusion of blood‐related products has yet to be determined.

Collectively, these efforts reflect a growing shift toward individualized recipient assessment, combining immunological risk stratification, ethical considerations, and biological screening of donors to ensure safe and effective xenotransplantation.

6. Immunosuppression

Immunosuppression remains an area of ongoing innovation and discussion in xenotransplantation. Although CD40–CD40L blockade has shown the most promising results in preclinical nonhuman primate (NHP) models, clinical translation remains limited by the scarcity of FDA‐approved agents. As the field looks for new pharmaceuticals to counteract the powerful anti‐pig immune response, it is worth considering novel approaches such as the CD40L‐activated B‐cell proliferation model developed to validate anti‐CD40/CD154 monoclonal antibodies for potential use in xenotransplantation [17]. On the other hand, conventional immunosuppressive regimens continue to demonstrate feasibility when carefully tailored. Mitchell et al. reported successful antibody‐directed therapy for presumed rejection in a pig heart xenograft recipient using standard agents [18]. Similarly, a study in Japanese monkeys demonstrated that species‐specific pharmacodynamic adjustments can ensure safe and effective immunosuppression [19].

To supplement the current arsenal of immunosuppressive agents, innovative methods of immune regulation and modulation have emerged. One notable strategy involved a novel IgM‐cleaving enzyme, which was shown to significantly reduce xenoreactive antibodies and prolong graft survival in NHPs [20]. Similar to IdeS, this new enzyme was capable of significantly decreasing the IgM xenoantibody levels. The feasability of repeated treatments and risks of post‐treatment rebounds have to be further investigated. An alternative approach is polymorphonuclear neutrophil (PMN) inhibition, which has been shown to be effective in blunting cytotoxicity against gene‐edited donor cells. Briefly, PMN inhibition was employed in engineered hypoimmune models to evade T cell, NK cell, and macrophage responses (cells are HLA‐depleted and overexpress immune‐inhibitory ligands like CD47, CD99, and CD200). This approach attenuated the innate cytotoxic response and improved the survival of pig cells when injected in a NHP model [21]. Finally, desensitization protocols using a combination of proteasome inhibition and co‐stimulation blockade were tested by the Minnesota group [22]. Although the sample size was limited, the regimen resulted in a reduction of xenoreactive antibody levels but no observed survival benefit.

The optimal immunosuppressive regimen in clinical xenotransplantation is still matter of debate. It is likely that a personalized immunosuppressive approach may be required based on organ type, genetic background, and recipient characteristics. In this regard, Singh et al. demonstrated that variation in immune response is a key factor determining survival and pathology of 10‐gene pig heart xenograft   in NHPs [23].

7. Organ Preservation

Similar to human allografts, xenografts have a significant potential for ex vivo interventions. While much of the field has focused on genetic engineering, ex vivo organ preservation and modulation offer strategies to reduce ischemia‐reperfusion injury (IRI) and optimize graft viability is  in xenotransplantation. Early 2025 provided multiple publications that looked at the topic of preservation strategy in xenotransplantation.

A study modeling infant cardiac xenotransplantation demonstrated that tailored preservation protocols–including rapid cooling and modified perfusate composition–reduced IRI in vulnerable recipients [24]. Similarly, normothermic machine perfusion (NMP) of porcine livers and lungs improved viability and function during extended storage [25]. In the event a xenograft cannot be transplanted immediately, preservation strategy becomes critical. A study comparing static cold storage and hypothermic machine perfusion following 5 h of cold ischemic time in pig‐to‐baboon kidney xenotransplantation found that all SCS‐preserved grafts underwent hyperacute rejection within 90 min, even in low‐sensitized recipients. In contrast, kidneys preserved with hypothermic machine perfusion successfully re‐perfused and maintained function for over 14 days–comparable to outcomes in grafts with minimal cold ischemic time. These findings highlight the porcine kidney's unique sensitivity to IRI and suggest that SCS is inadequate across xenogeneic barrier. This suggests that it may outperform static cold storage in cross‐species applications [26].

Akin to how machine perfusion changed the landscape of allotransplantation and significantly expanded the donor pool, xenotransplantation could follow a similar path–a topic highlighted by Nakamura et al. The authors emphasized the potential of liver xenografts to serve as a bridge to allotransplantation, highlighted the role of ex vivo perfusion in preserving organ viability, and discussed immune modulation techniques to improve cross‐species compatibility and clinical readiness [27].

8. Infectious Disease

Infectious risk will always remain a central challenge in xenotransplantation. In addition to the infectious disease white paper [4], Fishman et al. proposed a surveillance and management framework based on their experience with the first pig‐to‐human kidney xenotransplant [28]. Recent studies by Jhelum et al. [29] and Denner et al. [30] refined PCR‐based detection methods for PERV‐C, improving the accuracy of preclinical screening and enabling early identification of safe donor lines. Additionally, Denner et al. emphasized the value of humoral surveillance–such as anti‐PERV antibody screening–in detecting viral activation and pre‐empting immunologic injury in clinical recipients [30]. The importance of eliminating porcine cytomegalovirus (PCMV/PRV) has also been reinforced, given its association with early graft failure, further underscoring the need for virus‐free donor herds [31]. As such, comprehensive evaluation of donor pigs plays a critical role in clinical readiness.

Beyond diagnostics, ethical and regulatory discussions emphasized the importance of comprehensive viral screening in first‐in‐human trials. A recent mixed‐methods study highlighted recipients’ desire for transparent information about infectious risks when consenting to pig kidney trials [32]. Regulatory reviews further stressed that Expanded Access pathways must balance innovation with stringent infection control [33].

As we approach clinical trials, public and religious perspectives will shape risk perception. Surveys in the United State [34] and South Korea [35] revealed persistent concern over zoonotic disease, particularly among certain cultural and religious groups. These findings stress the need for public education alongside rigorous pathogen surveillance as the field progresses.

9. Ethics, Regulatory Challenges, and Public Perception

The clinical expansion of xenotransplantation continues to raise important ethical and regulatory questions. One of these is with regard to animal wellbeing. Public perception surveys across the United Sates, South Korea, and Muslim communities revealed that animal welfare is a key concern influencing xenotransplantation acceptance, particularly in religious and culturally sensitive populations [36]. These perspectives reinforce the need for transparent animal care practices and public education initiatives. While many studies have emphasized the importance of minimizing animal suffering through improved housing, surgical standards, and monitoring protocols, bioethical commentary continues to explore the concept of genetic disenhancement–altering animals to reduce their capacity for pain–as a possible compromise in early‐stage xenotransplantation.

Concurrent with the ongoing discussions surrounding the ethics of animal care and use in xenotransplantation, the human heart xenotransplantation case reignited discussions on informed consent, patient vulnerability, and oversight in early‐phase trials [32]. These concerns are particularly relevant in pediatric and decedent studies, where capacity and long‐term implications complicate trial design [37]. Updated IXA guidelines outlined regulatory frameworks for donor selection, trial governance, and long‐term monitoring, reinforcing the need for structured oversight as more clinical protocols emerge [2].

Public attitudes around xenotransplantation will also be important to understand as this will influence policy, funding, and trial participation. A US‐based national survey found that acceptance varies significantly based on religious belief, age, and ethnicity, with higher skepticism among minority groups and younger populations [38]. A similar study in South Korea echoed these concerns, revealing that unfamiliarity and fear of complications were key barriers to public support [35].

The acceptance of a porcine‐based medical therapy will be influenced by religious upbringing as well. A study in a predominantly Muslim population highlighted nuanced concerns related to religious permissibility and cultural values, emphasizing the need for tailored educational campaigns [36]. Ethical literature also underscored that patient trust is closely tied to transparent communication, particularly when novel risks–like zoonosis–are involved [41]. With regard to the criteria for recipient selection, recent ethical and policy‐focused publications examined this issue. New frameworks were proposed by Kögel et al. and others that emphasized a multicriteria approach for inclusion in early trials, balancing clinical urgency, immunological risk, and patient preferences. Patients with end‐stage organ failure who lack allotransplant options were discussed as potential candidates. This was ultimately reflected in clinical trial designs that prioritize patient autonomy and fully informed consent during eligibility assessment [41, 42]. Finally, regulatory frameworks–particularly the FDA's Expanded Access pathway–continue to shape xenotransplantation clinical trial design, highlighting the importance of discussions concerning the permissible intensity of immunosuppression [42, 43].

10. Patient Selection and Equity

Determining who should be eligible for early xenotransplantation trials remains a critical ethical and clinical issue [3, 44]. Recent cases, including the third genetically modified kidney xenotransplantation in a human, have focused on patients with no remaining treatment options, aligning with the principle of medical urgency [45]. A multicriteria model was proposed to guide inclusion based on clinical need, immunologic risk, and patient choice, aiming to ensure safety and fairness in trial enrollment [39, 40].

Equity concerns are especially pronounced in pediatric settings, where ethical complexities are amplified. Recent studies emphasize the need for transparent selection frameworks that balance benefit, consent, and long‐term impact [37, 46]. Additionally, public discussions have highlighted fears of inequity in access, especially for underserved populations, prompting calls for global access strategies and culturally sensitive outreach [43, 47]. The IXA's regulatory recommendations echoed these concerns, stressing that trial design must prioritize scientific rigor and social justice [3, 42, 48]. Xenotransplantation may also worsen systemic inequities if not guided by strong public oversight [49]. Alobaidi similarly warned that access to xenotransplantation may mirror and magnify existing transplant inequities [50].

11. Conclusion

From January to May 2025, xenotransplantation has continued its rapid transition from experimental science to clinical application. Advancements in immune modulation, donor engineering, preservation techniques, and ethical frameworks have broadened the field's potential across organs and patient populations. As early human trials expand and global interest grows, maintaining scientific rigor, transparency, and ethical accountability will be critical to sustaining momentum and public trust. The months ahead will likely be pivotal in defining xenotransplantation's place in modern medicine.

Importantly, this scientific momentum has been paralleled by the release of white papers and international position statements–most notably from the International IXA–that offer structured frameworks for addressing infection surveillance, preclinical readiness, informed consent, and recipient selection. These documents represent a collective consensus across research, clinical, and regulatory communities, helping to harmonize trial design and ensure safety and ethical integrity in first‐in‐human protocols. Their influence is already evident in expanded‐access programs and FDA guidance and in the design of upcoming clinical trials that now emphasize donor screening, pathogen surveillance, and multidisciplinary review boards.

Together, these scientific advances and policy documents mark a maturation point for the field–one in which clinical translation is no longer a theoretical goal but an operational reality. As stakeholders work to consolidate data from decedent, primate, and early living recipient models, the field is poised to redefine organ transplantation, not as a limited resource but as a scalable and ethically governed solution to global organ shortages.

Shirini K., Ladowski J. M., and Meier R. P. H., “Xenotransplantation Literature Update: January–June 2025.” Xenotransplantation 32, no. 4 (2025): 32, e70072. 10.1111/xen.70072