Manganese suppresses the development of oral leukoplakia by activating the immune response

Abstract Objective Manganese ion (Mn 2+ ) is reported to promote the antitumor immune response by activating the cGAS‐STING pathway, but it is unknown whether Mn 2+ can prevent the malignant transformation of precancerous lesions. The effects of Mn 2+ 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 Mn 2+ 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 Mn 2+ in this model. 4‐nitroquinoline oxide (4NQO)‐induced OLK mice were used to assess the role of Mn 2+ in suppressing OLK progression, and a novel Mn 2+ ‐loaded guanosine‐tannic acid hydrogel (G‐TA@Mn 2+ 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. Mn 2+ 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 Mn 2+ enhanced the anti‐OLK immune response by activating the cGAS‐STING pathway. Moreover, Mn 2+ suppressed the development of 4NQO–induced carcinogenesis in the mouse model. In addition, the G‐TA@Mn 2+ hydrogel had better anti‐OLK effects. Conclusions Mn 2+ enhanced the anti‐OLK immune response by activating the cGAS‐STING pathway, and the G‐TA@Mn 2+ hydrogel is a potential novel therapeutic approach for OLK treatment.