Is β-cell replacement enough? Rethinking stem cell-based therapies for diabetes

Diabetes mellitus is characterised by progressive loss or dysfunction of functional β-cell mass arising through distinct but overlapping mechanisms in type 1 and type 2 diabetes, including autoimmune-mediated destruction, metabolic stress, and microenvironmental dysfunction. Despite major advances in pharmacological and technological management, current therapies remain largely compensatory and have not consistently restored endogenous β-cell function. Stem cell–based approaches have therefore emerged as promising strategies to address the underlying pathophysiology of the disease. This review synthesises stem cell–based therapies across four complementary therapeutic components: (1) β-cell replacement through pluripotent stem cell differentiation and emerging platforms such as direct reprogramming and islet organoids; (2) systemic immune modulation or immune resetting via hematopoietic stem cell–based interventions and regulatory immune modulation; (3) local graft protection and microenvironmental repair mediated by mesenchymal stromal cells, extracellular vesicles, and biomaterial-based approaches; and (4) cell-intrinsic immune engineering to reduce immune recognition of transplanted cells. While β-cell replacement strategies have demonstrated significant progress toward generating functional insulin-producing cells, their clinical efficacy remains constrained by incomplete maturation, immune rejection, and limited engraftment. Immune resetting approaches provide mechanistic evidence for the potential reversibility of autoimmune dysfunction but are limited by toxicity and the lack of durable tolerance. In contrast, local paracrine and microenvironmental strategies exert immunomodulatory and cytoprotective effects that stabilise the islet microenvironment but do not directly restore β-cell mass. Cell-intrinsic immune engineering offers an alternative strategy to reduce immune recognition of transplanted cells, although long-term immune evasion, genomic safety, and graft durability remain important translational challenges. These findings indicate that single-modality approaches are unlikely to be sufficient to achieve durable disease modification. Instead, effective therapeutic strategies may require integrated, multi-axis interventions that combine β-cell replacement, immune modulation, and microenvironmental support. Emerging advances in genome engineering, biomaterial-based encapsulation, and extracellular vesicle engineering are likely to facilitate this transition toward coordinated regenerative therapies. This integrated framework provides a systems-level perspective on current limitations and future directions for stem cell-based treatment of diabetes mellitus.