Research on hypoxia-mediated macrophage polarization during the carcinogenesis of oral leukoplakia

doi:10.19439/j.sjos.2026.03.005

Abstract

Abstract: PURPOSE: To investigate the expression level of hypoxia-inducible factor-1α (HIF-1α) and its impact on macrophage polarization in the immune microenvironment during carcinogenesis of oral leukoplakia (OLK). METHODS: This study employed multiplex immunofluorescence to retrospectively analyze HIF-1α, inducible nitric oxide synthase (iNOS), and CD206 expression in 25 OLK and normal mucosal tissue samples. An in vitro co-culture system was conducted under hypoxic conditions with Leuk-1 and Raw 264.7 cells. Macrophage polarization dynamics were quantitatively assessed by detection of HIF-1α, iNOS, and CD206 expression levels. Subsequently, inhibitor of HIF-1α was used to validate its regulatory role. RESULTS: In a cohort of 25 OLK and normal mucosal tissue samples, iNOS⁺ cells demonstrated initial elevation during mild dysplasia but significantly decreased in severe dysplasia and oral squamous cell carcinoma (OSCC). Conversely, CD206⁺ and HIF-1α⁺ cells exhibited progressive accumulation throughout OLK malignant transformation. Macrophage polarization analysis revealed M1 polarization (CD206/iNOS ratio: 0.68±0.22 to 0.69±0.41) was presented in mild-to-moderate dysplasia, with marked M2 polarization emerging in advanced stages (3.27±1.64 to 5.82±1.32). Correlation analyses identified progressively strengthened associations between HIF-1α and CD206, iNOS, and M2 polarization during disease progression. In vitro experiments under hypoxic conditions confirmed positive correlations between HIF-1α expression and CD206/iNOS levels as well as M2 polarization, while HIF-1α inhibition significantly attenuated M2 polarization. These findings suggest hypoxia-mediated HIF-1α signaling may orchestrate macrophage phenotypic switching during oral carcinogenesis. CONCLUSIONS: During OLK malignant transformation, HIF-1α expression is progressively upregulated, driving the polarization shift of tissue macrophages from pro-inflammatory M1 to pro-tumorigenic M2 phenotypes.

Key words: Oral leukoplakia, Tumor-associated macrophages, Hypoxia-inducible factor-1α, Macrophage polarization, Hypoxic microenvironment

CLC Number:

R785.1

Zhao Xiaoxian, Zhang Chunye, Zhao Zhengyan, Zhang Ying, Wu Lan. Research on hypoxia-mediated macrophage polarization during the carcinogenesis of oral leukoplakia[J]. Shanghai Journal of Stomatology, 2026, 35(3): 252-257.

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