Ionizing Radiation-treated NRF2-deficient Cancer Cells Promote Type I Interferon Signaling in Immune Cells

Background/Aim: Nuclear factor erythroid-derived 2 -related factor -2 (NRF2) is a transcription factor that regulates stress response genes. It negatively regulates the immune system by acting as a transcriptional repressor of inflammatory genes or suppressing type I interferon (IFN) production pathways. NRF2 is often over -expressed in some tumors, including non -small cell lung cancer, and modulates these tumors via an immune -cold microenvironment. Thus, strategies to convert cold tumors into hot tumors are effective for cancer treatment. Materials and Methods: NRF2 was knocked -down or over -expressed in human cancer cells (A549, HeLa, H1299, H1650) and mouse mammary adenocarcinoma TS/A cells. Cells were irradiated or transfected with poly(I:C), and changes in type I IFN levels were examined using quantitative real-time polymerase chain reaction and western blotting. Cytosolic DNA was assayed via PicoGreen staining and immune and cancer cells were co -cultured. Results: Regulation of NRF2 expression altered type I IFN levels in the human lung cancer cell line A549 and several solid tumors. Down -regulation of NRF2 resulted in increased levels of cytosolic DNA and activated the cGAS-STING pathway. We confirmed that type I IFN was induced in NRF2-downregulated tumor cells using ionizing radiation (IR). Furthermore, when dendritic cells and macrophages were cocultured with IR -exposed NRF2 knockdown tumor cells, the immune cells produced more IFNB1 and CXCL10. Conclusion: The immunosuppressive tumor cell environment is improved by NRF2 down -regulation, and IR treatment may promote immune cell signaling activation.