Dual‐Epigenetically Relieving the MYC‐Correlated Immunosuppression via an Advanced Nano‐Radiosensitizer Potentiates Cancer Immuno‐Radiotherapy

Abstract Cancer cells can upregulate the MYC expression to repair the radiotherapy‐triggered DNA damage, aggravating therapeutic resistance and tumor immunosuppression. Epigenetic treatment targeting the MYC‐transcriptional abnormality may intensively solve this clinical problem. Herein, 5‐Aza (a DNA methyltransferase inhibitor) and ITF‐2357 (a histone deacetylase inhibitor) are engineered into a tungsten‐based nano‐radiosensitizer (PWAI), to suppress MYC rising and awaken robust radiotherapeutic antitumor immunity. Individual 5‐Aza depletes MYC expression but cannot efficiently awaken radiotherapeutic immunity. This drawback can be overcome by the addition of ITF‐2357, which triggers cancer cellular type I interferon (IFN‐I) signaling. Coupling 5‐Aza with ITF‐2357 ensures that PWAI does not evoke the treated model with high MYC‐related immune resistance while amplifying the radiotherapeutic tumor killing, and more importantly promotes the generation of IFN‐I signal‐related proteins involving IFN‐α and IFN‐β. Unlike the radiation treatment alone, PWAI‐triggered immuno‐radiotherapy remarkably enhances antitumor immune responses involving the tumor antigen presentation by dendritic cells, and improves intratumoral recruitment of cytotoxic T lymphocytes and their memory‐phenotype formation in 4T1 tumor‐bearing mice. Downgrading the radiotherapy‐induced MYC overexpression via the dual‐epigenetic reprogramming strategy may elicit a robust immuno‐radiotherapy.