Immune suppression, HLA-risk and potential future immune based targets of oral leukoplakia progression

Background Oral leukoplakia (OL) is the most common oral potentially malignant disorder and carries a non-trivial risk of malignant transformation. Biomarkers are sought to aid in identifying lesions with high risk for malignant transformation, yet none are currently validated. Recent success of immune based therapies in head and neck oncology highlights immune involvement in the progression of these diseases. The differential expression of classical and non-classical HLA molecules in oral leukoplakia are thought to contribute to their malignant transformation. To better evaluate the role HLA plays in oral pre-malignant lesions, a scoping review was performed. Methods A scoping review was conducted in accordance with the PRISMA guidelines across PubMed, EMBASE, and Web of Science. 293 studies were reviewed from 1989 to 2025. Results 15 studies were screened by title, then 5 original research abstracts were included. Samples studied ranged from n = 16 to n = 100. It was found that leukoplakia lesions had higher expressions of HLA-E, HLA-G, CircHLA-C, and HLA-DR. Conclusion The upregulation of non-classical HLA molecules, particularly HLA-G, HLA-E, and circHLA-C in oral leukoplakia, suggests an immunologic shift, potentially facilitating tumor immune evasion in oral leukoplakic lesions. HLA expression may serve as a potential biomarker for identifying pre-malignant oral lesions at increased risk of malignant transformation. Also, circHLA-C may provide a target for therapeutic intervention in high-risk oral premalignant lesions.