Hypoimmune stem cells and islets: hype or a true breakthrough in diabetes treatment?

Immune-resistant pancreatic islets hold great promise for advancing diabetes cell therapy. Two key approaches, hypoimmunogenic pluripotent stem cells (PSCs) and hypoimmunogenic cadaveric islets, aim to overcome immune rejection in islet transplantation. Human PSCs provide a versatile source of insulin-producing cells, but immune rejection remains a major barrier. Recent advances in gene-editing technologies have enabled the modification of PSCs and cadaveric islets to reduce their immunogenicity. These cells can be engineered to express human leukocyte antigen (HLA)-negative profiles, while overexpressing immunoregulatory factors such as CD47, PD-L1, and HLA-G to evade T cell and natural killer (NK) cell immune-mediated responses. These modifications aim to generate "off-the-shelf" islet cell therapies compatible with a wide range of patients, potentially eliminating the need for immunosuppressants. However, ensuring long-term safety and functionality remains a challenge. Potential risks such as immune escape, viral infections, and tumorigenicity must be carefully addressed through additional safety measures. This review explores different approaches for generating hypoimmunogenic islets, recent advances in overcoming immune rejection, and key hurdles that need to be addressed for widespread clinical use for patients with diabetes. It also compares the potential benefits and limitations of hypoimmunogenic cadaveric islets versus hPSC-derived islets, providing insights into their future clinical applications.