Cell therapy for type 1 diabetes: Tracing historical progress and exploring emerging technologies

Abstract

Type 1 diabetes remains an incurable autoimmune disease, and despite advances in insulin-delivery systems, many patients still face severe hypoglycemia, glucose variability, and psychological burden. Beta-cell replacement offers a transformative alternative, with allogeneic islet transplantation providing durable protection and improved quality of life, yet limited by donor availability and the need for immunosuppression. Stem cell–derived islet-like clusters are now reaching clinical milestones, showing promising insulin independence and glycemic control, while encapsulation, autologous induced pluripotent stem cells (iPSC)-derived therapies, and gene-edited “hypo-immune” cells aim to overcome immune barriers. Porcine islet xenotransplantation is also being revisited, although regulatory and immunological hurdles remain. Key challenges persist in cell delivery, engraftment, and long-term function. As cell therapy transitions from experimental proof-of-concept to clinical reality, success will require scalable manufacturing, safe and effective delivery, regulatory alignment, and patient-centered approaches to ensure broad and meaningful impact.

Type 1 diabetes (T1D) is still, in 2025, an incurable autoimmune disease affecting over 9 million people across the globe. Despite remarkable strides in insulin-delivery technologies (i.e., automated insulin-delivery [AID] systems), several patients continue to live with the daily threat of severe hypoglycemia, fluctuating glucose levels, and psychological burden. For these individuals, the idea of replacing lost beta cells rather than compensating for them has never felt more urgent and is now labeled as beta-cell replacement approach. This approach encompasses both pancreas transplantation, which has markedly improved over the past decades but remains a complex surgical procedure reserved for patients with limited comorbidities. In contrast, islet transplantation represents a minimally invasive cell therapy approach that can be offered to a broader range of patients. However, as islet therapies are regulated as advanced therapy medicinal products (ATMP) or “biological product,” their use is limited to specialized centers, making them largely inaccessible despite promising results.

Beyond the algorithm: why technology is not enough

AID systems, often labeled as “closed-loop,” have undoubtedly shifted the therapeutic landscape. They have improved continuous glucose-monitoring parameters (i.e., time in range 70–180 mg/dL), lowered HbA1c, and given patients more flexibility. Yet, even the best of these systems leaves a residual risk: in real-world studies, 9–17% of users still report severe hypoglycemic events ¹ . Perhaps more striking is the persistence of emotional distress: nearly one in two patients still show high scores on the PAID (Problem Area in Diabetes) scale ² . Bihormonal pumps have demonstrated significant reductions in both time spent in hypoglycemia and number of hypoglycemic events in randomized trials ³ . While devices can facilitate management, they do not restore the lost biology and require patient acceptance of both the technology and the use of such devices. Cell therapy offers something entirely different: the chance to reintroduce physiological insulin secretion and potentially stop exogeneous insulin administration.

Allogeneic islet transplantation: a mature but limited approach

Of all current cell-based strategies, allogeneic islet transplantation is by far the most advanced. Through years of careful clinical work, protocols for isolating and infusing pancreatic islets from deceased donors have been refined, and the benefits are now well documented. In multiple cohorts (e.g., from France, Switzerland, Canada, Italy, and the US), transplanted patients show robust outcomes: transient period of insulin independence, quality of life improvement, and a dramatic drop in severe hypoglycemia, with over 90% remaining protected a decade^4–6.

These are not just metabolic gains, a matched comparison between transplanted and non-transplanted patients showed fewer occurrence of a composite criteria (cardiovascular events, dialysis, amputation, death) without an increase in cancer risk despite the use of immunosuppressive treatment ⁷ . Nonetheless, the requirement for chronic immunosuppression remains a major limitation, exposing patients to increased risk of infections and other treatment-related complications.

But the Achilles’ heel of this approach is obvious: donor shortage. Each transplant typically requires islets from multiple pancreases. No matter how refined the technique, it cannot be scaled to meet global needs. A renewable cell source is a necessity.

Stem cell-derived islets: a milestone reached

Pluripotent stem cells, whether embryonic (ESC) or induced (iPSC), are now at the forefront of regenerative medicine, and in T1D, their potential is rapidly becoming a reality. Twenty-five years after the first publication of a cohort of islet transplant recipients, a new milestone has just been reached with the innovative cell therapy product zimislecel (formerly VX-880). This ATMP consisted in ESC-derived islet-like clusters improved HbA1c, elimination of severe hypoglycemia, and insulin independence in 83% (10/12) of patients 1 year after a single injection of zimislecel; the durability of this effect and the long-term safety remain under investigation ⁸ . The transplantation site in this phase I-II trial remains unchanged (the liver), meaning that these islets cannot be retrieved in case of complications, biopsies are not an option for diagnosing rejection, and they will be exposed to the same type of inflammatory and hypoxic stress as cadaveric islets.

Additional progress has been reported with encapsulated stem cell–derived β cells. A recent phase III trial ⁹ showed that macro-encapsulated pancreatic endoderm derivatives of human ESCs could generate clinically meaningful C-peptide secretion (≥0.1 nmol/L) in some patients with T1D, leading to improved glycemic control and reduced insulin requirements. Notably, one participant reached a time in range of 85% at 12 months, despite only 4% of the initial grafted cell mass remaining in retrieval devices. These findings demonstrate the feasibility of encapsulation but also underscore limitations in engraftment efficiency and long-term survival. A parallel trial (NCT05791201 with VX-264), which explored macro-encapsulation to avoid immunosuppression, was halted in early 2025. The challenges (oxygenation, diffusion barriers, fibrotic responses) remain unresolved, underscoring how far device design still has to go.

For the first time, we have clinical evidence that lab-grown islet-like clusters cells can engraft, survive, and restore endogenous insulin secretion in human recipients. But success also brings new questions. Will these cells hold up over the long term? Will we face oncologic transformation of these cells? Is chronic immunosuppression the price we have to pay? Or could future iterations bypass this entirely?

Induced pluripotent stem cells: the autologous frontier

iPSC-based approaches open the door to personalized therapy by reprogramming a patient’s own cells into insulin-secreting clusters, potentially sidestepping immune rejection, a once elegant idea. A handful of two cases have emerged: one involving a young woman with T1D and prior organ transplants ¹⁰ , and another in a man with longstanding type 2 diabetes ¹¹ . Both received iPSC-derived islets and showed striking improvements in glycemic control.

These are early days. Key challenges remain: how to ensure stable, mature beta-cell differentiation? How to monitor and mitigate risks of genomic instability or tumor formation? And in T1D, does reintroducing beta cells reignite the same autoimmune process that destroyed them?

Even if these questions are answered, scaling up autologous therapies is a logistical challenge of another magnitude, and transforming bespoke procedures into standardized platforms will demand close collaboration between scientists, regulators, and manufacturers. Moreover, the cost of such a personalized therapy may challenge its widespread use. In addition, the evidence to date is limited to individual case reports, highlighting that both efficacy and safety, including the risk of tumorigenicity, remain largely unknown and must be carefully evaluated in controlled trials.

Editing the immune system: the promise of “hypo-immune” cells

Another strategy gaining traction involves editing cells to make them invisible to the immune system. Using the CRISPR technology, researchers have generated ESC lines lacking human leukocyte antigen (HLA) molecules and overexpressing PD-L1, a protein that can dampen immune responses. These “hypo-immune” islets have shown promising results in non-human primate models, avoiding rejection without immunosuppression ¹² . A recent case report ¹³ described the transplantation of hypo-immune islets cells into a human patient, resulting in non-immune reaction and a trend to glycemic control improvement. If these efforts succeed, they could enable off-the-shelf cell products, bypassing the need for lifelong immunosuppressants. But safety and durability still need to be proven.

Islet xenotransplantation: an old hope entering a new phase

Porcine islet xenotransplantation has long been considered a potential solution to donor shortages. Thanks to recent advances in gene editing (e.g., removal of key xeno-antigens and expression of human-compatible proteins), the concept is regaining momentum. Early studies in primates show encouraging short-term results ¹⁴ . Yet in humans with T1D, clinical application remains out of reach, not only due to immunological barriers but also because of complex regulatory hurdles and ethical concerns surrounding cross-species transplantation as well as poor porcine islet insulin-secretion capabilities implying high graft volume. Moreover, the potential risk of porcine zoonotic virus transmission remains a formal safety consideration despite advances in screening and genome editing. Addressing these regulatory and ethical barriers will be crucial alongside scientific progress to bring porcine islet xenotransplantation closer to clinical practice. The path forward will require both scientific progress and societal consensus.

The delivery dilemma

Regardless of cell source (e.g., cadaveric islets, stem cells), delivery remains a critical obstacle. Microcapsules, macrodevices, and scaffold-based implants are all being tested, with different implantation sites explored, including the subcutaneous space, intraperitoneal cavity, omentum, and even vascularized sites. However, none have yet shown reliable, reproducible function in humans. The immune system, oxygen gradients, nutrient diffusion, fibrosis, and site-specific micro-environment all stand in the way.

In the end, success may lie in hybrid solutions with better materials, smarter devices, and biological engineering adapted to optimal implantation sites ¹⁵ .

A turning point

We are entering a new era in diabetes care. Cell therapy is no longer an experimental dream, it is a grounded, evidence-based intervention. Allogeneic islets have already changed lives, and the clinical success of stem-cell-derived islets is on the horizon. “Hypo-immune” platforms and autologous grafts are not far behind.

Importantly, the fundamental barriers are shifting. The biology is proven. What remains are technical and systemic hurdles: how to manufacture cells at scale, protect them from the immune system, deliver them effectively, and ensure long-term safety and functionality.

These challenges are not minor, but they are solvable. Addressing them will require more than just good science, it will take a coordinated effort across disciplines, the support of health authorities, sustained funding, and the courage of patients willing to step into the unknown.

As cell therapies approach clinical reality, patient priorities must also guide progress, including the burden of disease management and considerations of cost and access. Integrating these perspectives will be critical to ensure that scientific advances translate into meaningful improvements in patients’ lives.