Choi, HyeongjwaKwon, JuntaeCho, Min SoonSun, YifanZheng, XiaofengWang, JingBouker, Kerrie B.Casey, John L.Atkins, Michael B.Toretsky, JeffreyHan, Cecil2023-04-252023-04-252021Choi H, Kwon J, Cho MS, et al. Targeting DDX3X Triggers Antitumor Immunity via a dsRNA-Mediated Tumor-Intrinsic Type I Interferon Response. Cancer Res. 2021;81(13):3607-3620. doi:10.1158/0008-5472.CAN-20-3790https://hdl.handle.net/1805/32589Induction of nucleic-acid sensing-mediated type I interferon (IFN) has emerged as a novel approach to activate the immune system against cancer. Here we show that the depletion of DEAD-box RNA helicase 3X (DDX3X) triggers a tumor-intrinsic type I IFN response in breast cancer cells. Depletion or inhibition of DDX3X activity led to aberrant cytoplasmic accumulation of cellular endogenous double-stranded RNAs (dsRNA), which triggered type I IFN production through the melanoma differentiation-associated gene 5 (MDA5)-mediated dsRNA sensing pathway. Furthermore, DDX3X interacted with dsRNA-editing ADAR1 and dual depletion of DDX3X and ADAR1 synergistically activated the cytosolic dsRNA pathway in breast cancer cells. Loss of DDX3X in mouse mammary tumors enhanced anti-tumor activity by increasing the tumor-intrinsic type I IFN response, antigen presentation, and tumor-infiltration of cytotoxic T and dendritic cells. These findings may lead to the development of a novel therapeutic approach for breast cancer by targeting DDX3X in combination with immune checkpoint blockade.en-USPublisher PolicyDDX3XDouble-stranded RNAsType I interferonCancer immunityArticle