Mitochondrial Lon functions in protein quality control and stress response pathways in mammals. Lon also has been shown to be overexpressed in various types of cancer including colon cancer, prostate cancer and oral cancer. Recently, we observed that Lon overexpression promotes ROS-dependent NF-κB and interferon (IFN) signaling in oral cancer, suggesting that Lon may induce a NF-κB-dependent inflammatory response. Herein, we used microarray expression analysis to demonstrate that Lon overexpression induces the interferon-stimulated genes, such as ISG15, IRF7 and STAT1 in a ROS-dependent manner in OSCC. We further found that mitochondrial DNA is released into cytosol in the Lon-overexpressing oral cancer cells and Lon-ROS axis induced the cGAS-STING pathway, then the mtDNA transfers to extracellular space by exosomes. In addition, we observed that Lon overexpression induces the ROS-dependent expression of indoleamine 2,3 dioxygenase (IDO) in OSCC, which is involved in mtDNA-STING activation tumor tolerogenic response. Taken together, these results suggest that inflammation induced by Lon overexpression may have an immunosuppression effect on tumor microenvironment.
