International immunopharmacologyJun 28, 2025

Low-immune-response stem cells: A breakthrough for cell-based regeneration treatments

Updated Jan 20, 2026

Abstract

Hypoimmunogenic pluripotent stem cells (hPSCs) may enable safer, more sustainable cell-based therapies by reducing immune rejection.

hPSCs are engineered to reduce or eliminate major histocompatibility complex (MHC) molecules and upregulate immunomodulatory proteins.
These modifications may enhance immune evasion, potentially allowing for universal donor cells.
Compared to traditional cell therapies requiring lifelong immunosuppression, hPSC strategies could minimize risks of infection, malignancy, and drug toxicity.
Challenges remain, including the risk of tumor formation and unintended genetic changes associated with gene editing.
Recent strategies, like suicide gene systems, may improve the safety and functional stability of hPSC-derived therapies.

Simplified

Hypoimmunogenic pluripotent stem cells (hPSCs) represent a transformative innovation in regenerative medicine, offering solutions to the longstanding challenge of immune rejection in cell-based therapies. Through advanced gene-editing techniques, particularly CRISPR/Cas9, hPSCs are engineered to downregulate or eliminate the expression of major histocompatibility complex (MHC) molecules while upregulating immunomodulatory proteins such as HLA-G, PD-L1, and CD47. These modifications enhance immune evasion and create the foundation for universal donor cells. Compared to conventional cell therapies that rely on lifelong immunosuppression, hPSC-based strategies offer safer, more sustainable, and patient-friendly solutions by minimizing the risks of infection, malignancy, and drug toxicity. Beyond immune compatibility, critical challenges persist, including the risk of tumorigenicity, off-target genetic alterations, and ethical considerations surrounding genome editing. Recent advances, such as the integration of suicide gene systems and sensitive monitoring assays, offer promising strategies to enhance the safety and functional stability of hPSC-derived therapies. This review comprehensively discusses the molecular engineering of hPSCs, their biomedical applications, safety strategies, ethical implications, and the evolving regulatory frameworks needed for clinical translation. By addressing both the scientific and societal dimensions, hPSCs have the potential to revolutionize personalized and off-the-shelf regenerative treatments, provided that rigorous safeguards are implemented.

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Competing interests

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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