HLA-G is a non-classical major histocompatibility complex class I molecule that functions as an immune checkpoint molecule 1. Unlike classical HLA class I molecules, HLA-G has restricted tissue distribution and low polymorphism frequency 2. Its primary function involves immune tolerance through binding inhibitory receptors (including KIRs and ILT-2) on natural killer cells, T cells, B cells, and dendritic cells, thereby suppressing their effector functions 1. This immunosuppressive activity is physiologically beneficial at the maternal-fetal interface, where HLA-G expression on trophoblastic cells modulates maternal immune responses and promotes pregnancy tolerance 3. HLA-G operates through negative regulation of T cell proliferation and natural killer cell-mediated cytotoxicity 1. However, HLA-G expression carries significant pathological consequences. Tumor cells frequently express HLA-G (neo-expression), enabling immune evasion and correlating with poor prognosis across multiple cancer types including cervical and breast cancers 45. This dual nature—protective when expressed by transplants or fetuses, but harmful when expressed by tumors—positions HLA-G as both a target for promoting transplant tolerance and a therapeutic target for blocking tumor-mediated immune escape 1. Recent engineering strategies exploit HLA-G's immunosuppressive properties to generate hypoimmunogenic stem cells for allogeneic cell therapy 6.