Cancer Prevention By Augmenting Mhc-I Apm Via Ezh2 Inhibition

To elucidate the functional and molecular mechanisms underlying EZH2-mediated carcinogenesis in OLK and attenuation of antigen presentation. Additionally, this research aims to construct a biocompatible adhesive hydrogel loaded with EZH2 inhibitors and to investigate the potential of locally administering this hydrogel in OLK model to enhance MHC-I antigen presentation and inhibit the carcinogenesis of OPMDs. Immunohistochemistry, multiplex IHC, and single-cell sequencing demonstrated a strong correlation between EZH2 overexpression, severity of epithelial dysplasia, reduced antigen-processing machinery gene expression, and diminished CD8+ T-cell infiltration. In vitro WB and qPCR confirmed EZH2-mediated suppression of MHC-I-related antigen presentation. CUT&RUN assays elucidated that EZH2 epigenetically silences MHC-I genes via H3K27me3 modification, promoting immune escape and malignant transformation. A GSK126-loaded adhesive hydrogel (PPT@GSK126) synergized with local immunotherapy effectively inhibited tumor progression in vivo, highlighting its potential for chemoprevention. EZH2 may play a role in mediating H3K27me3 modifications within the promoter regions of critical MHC-I genes, consequently inhibiting antigen presentation in OPMDs. This inhibition is associated with an increase in the proportion of exhausted CD8+ T cells and a decrease in the proportion of functional CD8+ T cells, which may accelerate the malignant transformation of these disorders. The synergistic effect of PPT@GSK126 hydrogel combined with local immunotherapy is expected to serve as an effective strategy for improving the prognosis of HNSCC. As EZH2 is highly expressed in numerous precancers, PPT@GSK126 has broad application prospects for reducing these tumor burdens.