Manganese Suppresses the Development of Oral Leukoplakia by Activating the Immune Response

OBJECTIVE:Manganese ion (Mn2+ ) is reported to promote the antitumor immune response by activating the cGAS-STING pathway, but it is unknown whether Mn2+ can prevent the malignant transformation of precancerous lesions. The effects of Mn2+ in treating oral leukoplakia (OLK) were explored in this work.METHODS:Peripheral blood Mn analysis of the patients was performed using inductively coupled plasma atomic emission spectroscopy (ICP-AES). A coculture model of dendritic cells (DCs)/macrophages, CD8+ T cells, and dysplastic oral keratinocytes (DOKs) was employed to analyze the role and mechanism of Mn2+ in a simulated OLK immune microenvironment. Western blot, RT-PCR, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and lactate dehydrogenase (LDH) assays were adopted to detect the mechanism of Mn2+ in this model. 4-nitroquinoline oxide (4NQO)-induced OLK mice were used to assess the role of Mn2+ in suppressing OLK progression, and a novel Mn2+ -loaded guanosine-tannic acid hydrogel (G-TA@Mn2+ hydrogel) was fabricated and evaluated for its advantages in OLK therapy.RESULTS:The content of Mn in patients' peripheral blood was negatively related to the progression of OLK. Mn2+ promoted the maturation and antigen presentation of DCs and macrophages and enhanced the activation of CD8+ T cells in the coculture model, resulting in effective killing of DOKs. Mechanistic analysis found that Mn2+ enhanced the anti-OLK immune response by activating the cGAS-STING pathway. Moreover, Mn2+ suppressed the development of 4NQO-induced carcinogenesis in the mouse model. In addition, the G-TA@Mn2+ hydrogel had better anti-OLK effects.CONCLUSIONS:Mn2+ enhanced the anti-OLK immune response by activating the cGAS-STING pathway, and the G-TA@Mn2+ hydrogel is a potential novel therapeutic approach for OLK treatment.