While the BLA approval represents a major regulatory milestone, it does not address critical challenges that impede the widespread adoption of islet transplantation.

The shortage of viable donor pancreata has led to a significant gap between the number of patients that can benefit from the therapy and the availability of islets. Since this subject has been extensively reviewed, here, we only outline key progress related to the current practice of human islet transplantation (Fig. 4).

Solutions to solve islet cell source availability beyond the biologics license application (BLA)

Porcine islets are a promising option for human transplantation owing to their physiological similarity to human islets. They can address the critical shortage of human donor organs by providing a more abundant and scalable source, potentially reducing wait times through consistent availability. Genetic modifications in pigs are advancing to minimize immune rejection [23,24,25,26], including expressing human leukocyte antigen (HLA) molecules to decrease immune recognition, deleting the alpha-galactosidase gene to prevent immune responses to alpha-gal epitopes, and introducing genes that encode immunomodulatory proteins such as cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA4-Ig) or programmed death-ligand 1 (PD-L1). In addition, pigs can be engineered to express human complement regulators, such as cluster of differentiation 46 (CD46) or cluster of differentiation 55 (CD55), to protect islet cells from complement-mediated damage. Advanced gene-editing tools, such as CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9), are also being used to knock out pro-inflammatory genes or introduce genes promoting immune tolerance [27].

Preclinical studies using naïve and genetically modified pig islets have shown encouraging results, particularly in non-human primates [28,29,30]. These studies demonstrated that pig islets could survive and function in primates for extended periods, especially when combined with immunosuppressive therapy or encapsulation. Clinical trials using pig islets in humans began in 2009 in New Zealand, led by Living Cell Technology. These trials yielded promising outcomes, such as improved blood sugar control and reduced insulin requirements, though they did not achieve long-term graft function or complete insulin independence [31, 32]. Recently, an Investigational New Drug (IND) application for encapsulated pig islets has been approved for clinical trials (ClinicalTrials.gov NCT06575426), with results expected in 2025.

Despite its potential, xenotransplantation faces significant regulatory challenges, particularly regarding biosafety concerns. A primary issue is the risk of transmitting porcine endogenous retroviruses (PERVs). The FDA mandates stringent safety protocols and continuous monitoring for xenotransplantation trials. The future of xenotransplantation will depend on advancements in genetic engineering, enhanced immune protection strategies, and addressing ethical and safety concerns.

In the 1990s, research focused primarily on differentiating embryonic stem cells (ESCs) into insulin-producing beta-cells [33]. Progress accelerated with the advent of induced pluripotent stem cells (iPSCs), enabling the generation of beta cells from adult cells in 2006 [34]. Throughout the 2010s, advancements in differentiation protocols significantly improved the functionality of these cells, allowing them to more closely resemble natural insulin-producing beta cells and effectively normalize blood sugar levels in diabetic mice [35,36,37,38,39].

Successful studies have demonstrated that human pluripotent stem cell (hPSC)-derived islets can improve glycemic control and alleviate diabetes symptoms in non-human primates (NHPs) [40], underscoring their potential as a promising therapy for diabetes.

ViaCyte is testing PEC-Direct (Pancreatic Endocrine Cells Direct), which involves implanting stem cell-derived pancreatic progenitors in a semi-permeable device under the skin. These progenitors mature into insulin-producing beta cells, potentially reducing or eliminating the need for external insulin [41, 42]. In February 2022, ViaCyte and CRISPR Therapeutics announced Phase I clinical trials for VCTX210, a hESC-based therapy for T1D that does not require immunosuppression. The CyT49 human embryonic stem cell (hESC) line has been genetically engineered to lack the beta-2 microglobulin (B2M) gene, preventing expression of major histocompatibility complex (MHC) class I molecules, and to express a transgene encoding programmed death-ligand 1 (PD-L1) to protect against CD8+ cytotoxic T-cell attack. These modifications enhance immune evasion, potentially reducing the need for long-term immunosuppression and improving graft survival [43, 44].

In 2021, Vertex Pharmaceuticals initiated a clinical trial (VX-880) using beta cells differentiated from human pluripotent stem cells with immunosuppression. These cells are engineered to function like natural beta cells. At the American Diabetes Association’s 84th Scientific Session in 2024, Vertex reported that all twelve patients receiving a single VX-880 infusion exhibited islet engraftment and glucose-responsive insulin production by day 90. All patients showed improved glycemic control, with reduced or eliminated insulin use. The three patients with over a year of follow-up met the primary endpoint of eliminating severe hypoglycemic episodes (SHE) with HbA1c < 7.0% and the secondary endpoint of insulin independence. VX-880 was generally well tolerated, with mostly mild-to-moderate adverse events and no serious treatment-related complications. Two deaths were reported, but they were unrelated to VX-880. In addition, the VX-264 clinical trial from Vertex was designed to combine allogeneic human stem cell-derived islets with encapsulation technology to shield the cells from the recipient’s immune system.

On the basis of the chemically induced pluripotent stem cell (CiPSC) technology [40, 45,46,47], a recent study reported the 1-year outcomes of a patient with T1D who underwent autologous transplantation of chemically induced pluripotent stem cell-derived islets (CiPSC islets) beneath the abdominal anterior rectus sheath, using standard immunosuppression. The patient achieved sustained insulin independence within 75 days, with time-in-target glycemic range increasing from 43.18% at baseline to 96.21%, stabilizing at over 98% with an HbA1c of approximately 5% [45]. Two additional patients have been implanted, with results expected in 2025. This marks significant progress toward personalized cell therapy for T1D using CiPSCs. The study employed standard immunosuppression, despite implanting autologous CiPSC-derived islets, owing to potential risks, including residual allogeneic antigens, autoimmune recurrence, and inflammatory responses that could compromise graft survival. It is worth noting that different immunosuppression strategies may be required for stem cell-derived islet transplants compared with traditional islet transplants, considering factors such as alloimmune rejection, autoimmune recurrence, and potential off-target immune responses.

Several ongoing national and international clinical trials are listed on ClinicalTrials.gov, though no transplant outcomes have been reported to date. Some research efforts combine stem cell-derived islet transplantation with novel immunotherapies aimed at retraining the immune system to tolerate beta cells, an approach that has been well-reviewed elsewhere [48]. While stem cell-based therapies have demonstrated considerable benefits for glycemic control, challenges remain, including immune rejection, long-term graft function, in vivo cell maturation, efficacy and safety concerns, and high manufacturing costs.

Stem cell-based therapies for diabetes will face stricter regulatory scrutiny than human islet transplants owing to safety concerns, such as the risk of tumor formation and genetic instability (https://www.isscr.org). Genetic modifications, long-term outcomes, and potential immunogenicity will require rigorous testing. Manufacturing processes for stem cells and their derivatives must meet high standards for quality control and consistency. Ethical concerns, particularly regarding the sourcing of stem cells, will also influence regulations. Regulatory agencies will demand extensive preclinical and clinical data to ensure the safety, efficacy, and ethical compliance of these therapies before they are approved for widespread use.

In human islet transplantation, immune rejection occurs because the recipient’s immune system recognizes the transplanted allogeneic islet grafts as foreign and attacks them. Without immunosuppression, islet grafts will be rejected, and function will be lost. Recently, it has shown that recurrent autoimmunity is a critical factor in islet graft loss, as seen in pancreas transplantation, where it may also trigger alloimmune responses [49]. Notably, a retrospective study suggests that HLA-DQ8 positivity may be associated with improved C-peptide levels, possibly indicating a role in immune tolerance [50]. Further investigation is needed to clarify the mechanisms and optimize patient selection. In the last three decades, various immune-evasive strategies have been applied for preventing islet graft loss (Fig. 5).

Immuno-evasive strategies in islet transplantation. iPSC-derived islet, induced pluripotent stem cell-derived islet-like cell; ciPSC, chemically induced pluripotent stem cell

The concept of islet microencapsulation originated in the 1970s, with early research focusing on alginate, a biocompatible polymer, to form a semi-permeable membrane that allows insulin and nutrients to pass through while blocking immune cells and antibodies [51]. In the 1980s and 1990s, advancements in alginate-based encapsulation techniques demonstrated promise. However, fibrosis (formation of tissue overgrowth around the capsules) remained a significant challenge, limiting long-term islet function [52,53,54]. Clinical trials demonstrated short-term protection, but often failed due to capsule surface fibrotic overgrowth on the capsule surface [55]. From the 2010s onward, new encapsulation strategies have emerged, focusing on reducing fibrosis and improving islet survival. These include advanced biocompatible materials, nanotechnologies such as ultra-thin coatings designed to be more biocompatible or durable, and new transplant sites [56,57,58,59,60,61,62].

Macrodevices are another approach to implantable devices that house clusters of islets. Macrodevices have shown promise in preclinical studies as a strategy to shield transplanted islets or stem cell-derived islets from immune-mediated attack, potentially reducing or eliminating the need for systemic immunosuppression. One notable example is the TheraCyte device, which uses a semi-permeable membrane to encase the islets. It has shown some success in both preclinical and clinical trials, particularly in improving long-term islet survival and function [63,64,65]. Another promising macrodevice is the Beta-O2 device, which features an oxygen reservoir that sustains islet function by providing a steady oxygen supply. This method has demonstrated superior outcomes in maintaining islet viability and function [66,67,68]. Implantable scaffolds, made from biocompatible materials, encourage vascularization around the islets, enhancing their survival and insulin production [69]. Using alginate fibers for islet encapsulation is an innovative approach that utilizes modified alginate formulations and combination materials to improve biocompatibility and reduce immune responses [70,71,72]. These advancements have shown promising preclinical results for islet transplant outcomes but have not been demonstrated in human clinical trials.

Ongoing clinical trials are investigating advanced polymers, oxygen-releasing agents, bioengineered scaffolds, and xenogeneic tissues to enhance islet transplantation availability and effectiveness, potentially eliminating the need for lifelong immunosuppression.

Gene editing tools, such as CRISPR-Cas9, are transforming islet biologics and stem cell-derived islets by enabling precise genetic modifications to enhance safety, efficacy, and immune evasion. CRISPR-Cas9 targets specific DNA sequences, creating double-strand breaks to allow targeted changes. This technique’s precision, efficiency, and versatility make it a revolutionary tool for genetic research and medical treatments. The application of these genetic modifications is to reduce islet immune responses, improve islet functionality, and increase the efficiency of differentiating stem cells into insulin-producing cells.

Traditional immune-evasive strategies, such as immunoisolation devices, immunosuppressive drugs, and tolerance induction techniques, have been used to improve graft survival and function. However, gene editing introduces new possibilities by directly altering the islet cells’ genetic makeup. For example, deleting genes responsible for expressing MHC class I molecules and co-stimulatory signals can reduce the immune system’s ability to recognize and attack the islets. One study showed that deleting polymorphic human leukocyte antigens (HLAs) in human pluripotent stem cells (hPSCs) significantly reduced natural killer (NK) cell activity and T-cell-mediated immune responses in humanized mouse models, enhancing the survival of stem cell-derived islet cells [73].

In addition, other studies have successfully engineered hypoimmune islets (e.g., B2M–/–, CIITA–/–, CD47+) in rhesus macaques, demonstrating long-term survival and insulin independence without immunosuppression [74]. Furthermore, researchers have enhanced protection against rejection by genetically engineering stem cell-derived islets to secrete immunomodulatory cytokines such as interleukin (IL)-10, transforming growth factor (TGF)-β, and IL-2, which promote a tolerogenic microenvironment and recruit regulatory T cells to the graft site [75]. These gene-edited islets demonstrated resistance to rejection and successfully reversed diabetes in animal models.