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HLA\u2010G 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\u2010G expression contributes to tumor immune evasion and influences clinical outcomes in patients with leukemia, lymphoma, and multiple myeloma. Genetic variability within the HLA\u2010G gene, particularly polymorphisms located in regulatory regions such as the 14\u2010base 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\u2010bound and soluble HLA\u2010G, correlating with impaired immune surveillance and reduced survival, particularly in chronic lymphocytic leukemia. Moreover, HLA\u2010G expressions may be modulated by inflammatory cytokines, such as interferon\u2010\u03b3, further shaping the immunosuppressive tumor microenvironment. By functioning as a nonclassical immune checkpoint, HLA\u2010G represents a promising target for innovative immunotherapeutic strategies, including immune checkpoint blockade combinations and chimeric antigen receptor (CAR)\u2010T cell approaches directed against HLA\u2010G\u2010expressing malignant cells. In this review, we summarize current knowledge regarding HLA\u2010G expression, genetic polymorphisms, and immunoregulatory mechanisms in hematological malignancies, highlighting their clinical and translational implications. Improved understanding of HLA\u2010G\u2010mediated immune modulation may contribute to the development of novel prognostic biomarkers and therapeutic strategies aimed at restoring effective antitumor immunity.<\/jats:p>","DOI":"10.1155\/jimr\/8747974","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T04:40:46Z","timestamp":1777956046000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["HLA\u2010G in Hematological Malignancies: Immunoregulatory Mechanisms and Implications for Immune Evasion and Immunotherapy"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1471-4472","authenticated-orcid":false,"given":"Tha\u00eds Lohana Chanel Pereira","family":"Ribeiro","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6110-7766","authenticated-orcid":false,"given":"Glenda 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