Engineering the ‘one-for-all’ cell: Molecular approaches to universal hypoimmunogenic pluripotent stem cells

The ground-breaking discovery of induced pluripotent stem cell (iPSC) technology has revolutionized regenerative medicine by providing an unlimited source of patient-specific cells capable of differentiating into any cell type. However, immune rejection following allogeneic transplantation remains a fundamental barrier to the widespread clinical implementation due to human leukocyte antigen (HLA) mismatches between donors and recipients. While current clinical studies are limited to HLA-matched approaches using autologous or HLA homozygous iPSC-derived grafts, practical constraints of time, cost, and scalability necessitate developing truly universal hypoimmunogenic iPSCs. This review examines molecular strategies for engineering universal iPSCs that can evade immune recognition through targeted genetic modifications. HLA class I elimination via B2M knockout effectively prevents CD8+T cell activation but renders cells vulnerable to NK cell-mediated "missing self" recognition. Alternative approaches include selective HLA targeting with HLA-C retention, which maintains NK cell inhibition while achieving substantial T cell evasion, and HLA class II elimination through CIITA knockout to prevent CD4+T cell activation. Addressing NK cell-mediated rejection requires complementary strategies including the introduction of NK inhibitory ligands such as HLA-E, HLA-G, and CD47. The most promising approaches utilize comprehensive combination strategies that simultaneously eliminate HLA class I and II molecules while incorporating multiple immune evasion mechanisms. Future directions include advanced gene editing technologies, inducible safety systems, and sophisticated computational modeling to optimize immune compatibility. These molecular engineering approaches represent a transformative pathway toward truly universal donor cells capable of transplantation without immune rejection, potentially revolutionizing the accessibility and clinical impact of iPSC-based regenerative medicine.