Type 1 diabetes (T1D) is driven by autoimmune destruction of pancreatic β-cells and remains incurable despite major advances in insulin delivery and glucose-monitoring technologies. Transplantation of primary islets or stem cell-derived β-like cells offers a promising route to physiological glycemic control; however, durable engraftment remains limited by complex immune rejection. Unlike classical solid organ transplantation, β-cell replacement in T1D confronts a uniquely intertwined set of immunological barriers, including innate inflammatory activation, adaptive alloimmunity, persistent humoral responses, and recurrent autoimmune memory, further exacerbated by as-yet undefined factors that disrupt the native islet microenvironment. These overlapping effector pathways help explain why single-axis immunosuppressive or physical shielding strategies have not achieved long-term protection. In this review, we synthesize current mechanistic insights into the immune processes that limit β-cell graft survival and organize emerging therapeutic strategies according to the rejection pathways they target. We discuss advances in graft-intrinsic immune engineering, local graft-adjacent immunomodulation, and systemic immune interventions aimed at mitigating innate inflammation, cellular and humoral immunity, and autoimmune recurrence. We further highlight translational progress, safety considerations, and regulatory challenges associated with these approaches.
Type 1 diabetes (T1D) is driven by autoimmune destruction of pancreatic β-cells and remains incurable despite major advances in insulin delivery and glucose-monitoring technologies. Transplantation of primary islets or stem cell-derived β-like cells offers a promising route to physiological glycemic control; however, durable engraftment remains limited by complex immune rejection. Unlike classical solid organ transplantation, β-cell replacement in T1D confronts a uniquely intertwined set of immunological barriers, including innate inflammatory activation, adaptive alloimmunity, persistent humoral responses, and recurrent autoimmune memory, further exacerbated by as-yet undefined factors that disrupt the native islet microenvironment. These overlapping effector pathways help explain why single-axis immunosuppressive or physical shielding strategies have not achieved long-term protection. In this review, we synthesize current mechanistic insights into the immune processes that limit β-cell graft survival and organize emerging therapeutic strategies according to the rejection pathways they target. We discuss advances in graft-intrinsic immune engineering, local graft-adjacent immunomodulation, and systemic immune interventions aimed at mitigating innate inflammation, cellular and humoral immunity, and autoimmune recurrence. We further highlight translational progress, safety considerations, and regulatory challenges associated with these approaches. Collectively, this mechanistic perspective provides a rational framework for designing coordinated immunomodulatory strategies to enable durable, immune-compatible β-cell replacement for T1D.