Pancreatic islet transplantation (IT) has emerged as a promising treatment for diabetes, particularly Type 1 Diabetes (T1D), by restoring endogenous insulin secretion and improving long-term outcomes. However, the procedure faces significant challenges, including organ shortage and immune rejection. Recent advancements have addressed these issues through the use of stem cell-derived and porcine islet cells, as well as novel transplant sites and immunological strategies. **Current Advances:** 1. **Stem Cell-Derived Islet β-Cells:** Research has focused on differentiating embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) into insulin-producing β-cells. These cells have shown potential in both in vitro differentiation and clinical trials, with some studies demonstrating successful insulin secretion and improved glycemic control. 2. **Porcine Islet Xenotransplantation:** Xenotransplantation using porcine islets offers a readily available source of islets, with pig insulin being highly similar to human insulin. Studies have shown that porcine islets can function in non-human primates, but challenges such as graft rejection and zoonotic infections remain. 3. **Novel Transplant Sites:** Researchers are exploring alternative transplant sites like the subcutaneous space and the greater omentum, which offer advantages over the traditional portal vein infusion method, including reduced immune rejection and better survival rates. 4. **Immunological Strategies:** Co-transplantation of mesenchymal stem cells (MSCs) and regulatory T cells (Tregs) with islet cells has shown promise in reducing immune rejection and improving islet function. Islet encapsulation technology, which uses biomaterials to protect islets from the immune system, is also under active development. **Challenges and Future Directions:** 1. **Organ Shortage:** The primary challenge is the limited availability of pancreatic islets, which can be addressed through stem cell-derived and porcine islet sources. 2. **Immune Rejection:** Immunosuppressive therapy is essential but has side effects. New strategies, such as MSC/Treg co-transplantation and islet encapsulation, aim to minimize the need for immunosuppression. 3. **Transplant Site Selection:** Optimal transplant sites, such as the subcutaneous space and the greater omentum, are being explored to improve islet survival and function. 4. **Immunological Reactions:** Further research is needed to optimize immunosuppressive protocols and develop more effective strategies to prevent immune rejection. In conclusion, while IT has shown significant promise in treating diabetes, ongoing challenges must be addressed to fully realize its potential. Advances in stem cell technology, xenotransplantation, and immunological strategies are expected to drive the development of more effective and safer IT procedures in the future.Pancreatic islet transplantation (IT) has emerged as a promising treatment for diabetes, particularly Type 1 Diabetes (T1D), by restoring endogenous insulin secretion and improving long-term outcomes. However, the procedure faces significant challenges, including organ shortage and immune rejection. Recent advancements have addressed these issues through the use of stem cell-derived and porcine islet cells, as well as novel transplant sites and immunological strategies. **Current Advances:** 1. **Stem Cell-Derived Islet β-Cells:** Research has focused on differentiating embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) into insulin-producing β-cells. These cells have shown potential in both in vitro differentiation and clinical trials, with some studies demonstrating successful insulin secretion and improved glycemic control. 2. **Porcine Islet Xenotransplantation:** Xenotransplantation using porcine islets offers a readily available source of islets, with pig insulin being highly similar to human insulin. Studies have shown that porcine islets can function in non-human primates, but challenges such as graft rejection and zoonotic infections remain. 3. **Novel Transplant Sites:** Researchers are exploring alternative transplant sites like the subcutaneous space and the greater omentum, which offer advantages over the traditional portal vein infusion method, including reduced immune rejection and better survival rates. 4. **Immunological Strategies:** Co-transplantation of mesenchymal stem cells (MSCs) and regulatory T cells (Tregs) with islet cells has shown promise in reducing immune rejection and improving islet function. Islet encapsulation technology, which uses biomaterials to protect islets from the immune system, is also under active development. **Challenges and Future Directions:** 1. **Organ Shortage:** The primary challenge is the limited availability of pancreatic islets, which can be addressed through stem cell-derived and porcine islet sources. 2. **Immune Rejection:** Immunosuppressive therapy is essential but has side effects. New strategies, such as MSC/Treg co-transplantation and islet encapsulation, aim to minimize the need for immunosuppression. 3. **Transplant Site Selection:** Optimal transplant sites, such as the subcutaneous space and the greater omentum, are being explored to improve islet survival and function. 4. **Immunological Reactions:** Further research is needed to optimize immunosuppressive protocols and develop more effective strategies to prevent immune rejection. In conclusion, while IT has shown significant promise in treating diabetes, ongoing challenges must be addressed to fully realize its potential. Advances in stem cell technology, xenotransplantation, and immunological strategies are expected to drive the development of more effective and safer IT procedures in the future.