Immune-evasive stem cells: engineering tolerance and reprogramming microenvironments for regenerative therapy

Stem cell transplantation (SCT) holds significant promise for regenerative medicine, yet immune rejection remains a major obstacle. To address this, recent advances leverage CRISPR/Cas9 to engineer hypoimmunogenic induced pluripotent stem cells. These modified cells lack classical immune recognition markers (HLA class I/II) yet retain immune-tolerant molecules such as HLA-E, HLA-G, and CD47, enabling their universal use across different individuals. Additionally, mesenchymal stem cell-derived exosomes and immune checkpoint modulators (e.g., PD-L1) have shown clinical effectiveness by reducing graft-versus-host disease and autoimmune reactions. They achieve this through mechanisms such as suppressing inflammatory T-cell activation, promoting regulatory T-cell expansion, and modulating macrophage polarization. Despite these advances, several challenges remain. One key concern is the potential tumorigenic risk caused by genomic instability during genome editing and long-term cell expansion. Emerging precision editing platforms, including base editing and prime editing, provide strategies to reduce double-strand DNA break-induced chromosomal rearrangements and improve genomic safety. Future research priorities include integrating AI-based immune profiling, precision genome editing, and advanced 3D-bioprinting technologies. Together, these innovations represent a paradigm shift toward developing safer, more effective, universally compatible stem cell therapies for diseases previously deemed untreatable.