Advances in stem cell-derived β-cell replacement therapy for T2D

Pancreatic β-cell dysfunction is a central contributor to the pathogenesis of type 2 diabetes (T2D). During T2D progression, β-cells undergo a transition from functional compensation to decompensation. Therefore, restoring or preserving functional β-cell mass represents a potential therapeutic strategy to slow disease progression. However, adult islets have limited endogenous regenerative capacity, and donor scarcity remains a major barrier to clinical islet transplantation. Stem cell-derived β cells (SC-β cells) have emerged as a promising exogenous cell replacement strategy for reversing hyperglycemia in type 1 diabetes (T1D), but their application in T2D is challenged by insulin resistance and glucolipotoxic stress. A first-in-human study reported the transplantation of autologous endoderm stem cell-derived islet organoids (E-islets) into a patient with advanced T2D, providing initial clinical evidence supporting the feasibility of exogenous SC-β cell replacement therapy in T2D. Notably, these E-islets recapitulated the composition and function of native human islets, suggesting their potential to restore insulin secretion under the metabolic stress conditions of T2D. In this review, we systematically outline the basic research and clinical advances in β-cell replacement therapy for T2D treatment, from the generation of SC-β cells to the engineering of complex islet organoids. Furthermore, we discuss key challenges limiting graft survival and long-term function, together with strategies including advanced 3D bioprinting, genetic modification, pharmacological preconditioning, co-transplantation with supportive cells or anti-T2D drugs, and pro-survival scaffolds. Collectively, this review summarizes current progress and discusses future perspectives on integrating bioengineering strategies and multi-omics approaches to advance exogenous SC-β cell replacement as a promising therapeutic strategy for T2D.