Li, XiaoguangLiu, ZhidaZhang, AnliHan, ChuanhuiShen, AijunJiang, LingxiangBoothman, David A.Qiao, JianWang, YangHuang, XiumeiFu, Yang-Xin2019-09-052019-09-052019-07-19Li, X., Liu, Z., Zhang, A., Han, C., Shen, A., Jiang, L., … Fu, Y. X. (2019). NQO1 targeting prodrug triggers innate sensing to overcome checkpoint blockade resistance. Nature communications, 10(1), 3251. doi:10.1038/s41467-019-11238-1https://hdl.handle.net/1805/20798Lack of proper innate sensing inside tumor microenvironment (TME) limits T cell-targeted immunotherapy. NAD(P)H:quinone oxidoreductase 1 (NQO1) is highly enriched in multiple tumor types and has emerged as a promising target for direct tumor-killing. Here, we demonstrate that NQO1-targeting prodrug β-lapachone triggers tumor-selective innate sensing leading to T cell-dependent tumor control. β-Lapachone is catalyzed and bioactivated by NQO1 to generate ROS in NQO1high tumor cells triggering oxidative stress and release of the damage signals for innate sensing. β-Lapachone-induced high mobility group box 1 (HMGB1) release activates the host TLR4/MyD88/type I interferon pathway and Batf3 dendritic cell-dependent cross-priming to bridge innate and adaptive immune responses against the tumor. Furthermore, targeting NQO1 is very potent to trigger innate sensing for T cell re-activation to overcome checkpoint blockade resistance in well-established tumors. Our study reveals that targeting NQO1 potently triggers innate sensing within TME that synergizes with immunotherapy to overcome adaptive resistance.en-USAttribution-NonCommercial-NoDerivs 3.0 United StatesImmunologyCancerArticle