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Human leukocyte antigen G (HLA-G) is a nonclassical major histocompatibility complex class I molecule whose increased expression has been consistently associated with unfavorable prognosis in solid tumors and has emerged as a potential immunotherapeutic target in hematological malignancies. HLA-G exhibits limited genetic diversity and generates multiple isoforms that play a critical role in immune tolerance, being physiologically expressed in immunoprivileged tissues and aberrantly upregulated in a variety of pathological conditions, including cancer. Accumulating evidence indicates that elevated HLA-G expression contributes to tumor immune evasion and influences clinical outcomes in patients with leukemia, lymphoma, and multiple myeloma. Genetic variability within the HLA-G gene, particularly polymorphisms located in regulatory regions such as the 14-base pair insertion/deletion, has been associated with cancer susceptibility, disease progression, and adverse prognosis. In hematological malignancies, specific genotypes, including the homozygous deletion variant, have been linked to increased levels of membrane-bound and soluble HLA-G, correlating with impaired immune surveillance and reduced survival, particularly in chronic lymphocytic leukemia. Moreover, HLA-G expressions may be modulated by inflammatory cytokines, such as interferon-γ, further shaping the immunosuppressive tumor microenvironment. By functioning as a nonclassical immune checkpoint, HLA-G represents a promising target for innovative immunotherapeutic strategies, including immune checkpoint blockade combinations and chimeric antigen receptor (CAR)-T cell approaches directed against HLA-G-expressing malignant cells. In this review, we summarize current knowledge regarding HLA-G expression, genetic polymorphisms, and immunoregulatory mechanisms in hematological malignancies, highlighting their clinical and translational implications. Improved understanding of HLA-G-mediated immune modulation may contribute to the development of novel prognostic biomarkers and therapeutic strategies aimed at restoring effective antitumor immunity.