The human leukocyte antigen G (HLA-G) is a non-classical MHC class I molecule involved in immune tolerance, primarily expressed in immune-privileged tissues like the placenta, thymus, and certain tumors. Unlike classical HLA molecules, HLA-G exhibits limited polymorphism and alternative splicing forms (membrane-bound and soluble isoforms). It interacts with inhibitory receptors (e.g., LILRB1. LILRB2. KIR2DL4) on immune cells, suppressing NK cell cytotoxicity, T-cell responses, and dendritic cell maturation. This immunomodulatory role is critical in maternal-fetal tolerance, organ transplantation, and tumor immune evasion. HLA-G antibodies are tools to detect HLA-G expression in research and clinical settings. Their applications include studying HLA-G's role in pregnancy complications, autoimmune diseases, cancer progression, and transplant rejection. In cancer, HLA-G overexpression correlates with poor prognosis, making it a potential therapeutic target. Therapeutic antibodies blocking HLAG/receptor interactions or targeting HLA-G-expressing cells are under exploration. However, challenges remain in standardizing detection methods due to HLA-G's isoform diversity and low expression levels in physiological conditions. Recent studies also explore HLA-G as a biomarker for liquid biopsies or immune checkpoint inhibitor efficacy prediction.