Genetically engineered hypoimmunogenic iPSCs: Strategies and considerations for clinical applications

Induced pluripotent stem cell (iPSC)-based therapies are rapidly advancing toward clinical implementation, with increasing numbers of trials and approvals for allogeneic iPSC-derived cell products. However, immune rejection remains a major barrier to the broad application of "off-the-shelf" allogeneic cell therapies for various diseases and injuries. With current advances in genetic engineering technologies, including genome editing, it is possible to establish a low-immunogenic cell product by disrupting immune recognition molecules and by overexpressing immunosuppressive factors. This review provides a comprehensive overview of current genetic engineering strategies for generating hypoimmunogenic iPS cells. Because multiplex genome editing and transgene integration may raise safety concerns, we further outline quality-control considerations for clinical-grade hypoimmunogenic iPSC products, including assessment of on-target outcomes, off-target mutations, structural variants, chromosomal abnormalities, residual editing components, and vector-related risks. Finally, we review current clinical development of genetically engineered hypoimmunogenic iPSC-derived products and discuss future challenges, including the importance of safety profiling and international regulatory harmonization. Understanding the advantages and limitations of each engineering and validation strategy will be critical for translating hypoimmunogenic iPSCs into safe, effective, and globally accessible regenerative therapies.