Gene-edited hypoimmune islets as a cure for type 1 diabetes: a review of the immunological challenges.

INTRODUCTION: Islet transplantation has long been considered a potential long-term treatment for type 1 diabetes mellitus (T1DM); however, the need for systemic immunosuppression has limited its clinical utility due to associated toxicity. Gene-edited hypoimmune islets represent a promising immunosuppression-free alternative. Recent first-in-human data demonstrating short-term engraftment and C-peptide production without immunosuppression, with 12-week immune monitoring and extended 14-month follow-up, provide an important proof-of-concept. However, whether short-term immune evasion can translate into durable long-term graft survival remains unclear. AREAS COVERED: We critically evaluate current preclinical and clinical evidence from 2019 to 2026 for gene-edited hypoimmune islets, highlighting key immunological vulnerabilities that may emerge over time. EXPERT OPINION: The central question is no longer whether these islets can evade acute rejection, but whether they can sustain this evasion and efficacy long-term against the human immune system. Several theoretical mechanisms may contribute to delayed graft injury: indirect allorecognition (particularly non-HLA antibody formation), persistence of autoreactive immune memory, β-cell stress-induced neoantigen formation, and susceptibility to viral infection. Durable graft survival will likely require multimodal approaches combining gene-edited islets with adjunct immunomodulation (e.g. teplizumab, low-dose ATG, tegoprubart) and metabolic support. If these long-term challenges can be overcome, gene-edited hypoimmune islets could transform T1DM treatment paradigms.