Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75235, USA.
School of Public Health, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
Nat Commun. 2019 Jul 19;10(1):3251. doi: 10.1038/s41467-019-11238-1.
Lack 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 NQO1 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.
肿瘤微环境（TME）中缺乏适当的固有感应限制了针对 T 细胞的免疫疗法。烟酰胺腺嘌呤二核苷酸（磷酸）：醌氧化还原酶 1（NQO1）在多种肿瘤类型中高度富集，已成为直接杀伤肿瘤的有前途的靶点。在这里，我们证明 NQO1 靶向前药 β-拉帕醌触发肿瘤选择性固有感应，导致依赖 T 细胞的肿瘤控制。β-拉帕醌被 NQO1 催化和生物激活，在 NQO1 肿瘤细胞中生成 ROS，引发氧化应激和损伤信号释放，用于固有感应。β-拉帕醌诱导的高迁移率族蛋白 B1（HMGB1）释放激活宿主 TLR4/MyD88/Ⅰ型干扰素途径和 Batf3 树突状细胞依赖性交叉呈递，以桥接针对肿瘤的固有和适应性免疫反应。此外，靶向 NQO1 非常有效地触发固有感应，以重新激活 T 细胞，从而克服已建立的肿瘤中检查点阻断的耐药性。我们的研究表明，靶向 NQO1 可有效地在 TME 中触发固有感应，与免疫疗法协同作用，克服适应性耐药性。
