| First Author | Li X | Year | 2019 |
| Journal | Nat Commun | Volume | 10 |
| Issue | 1 | Pages | 3251 |
| PubMed ID | 31324798 | Mgi Jnum | J:279473 |
| Mgi Id | MGI:6362516 | Doi | 10.1038/s41467-019-11238-1 |
| Citation | Li X, et al. (2019) NQO1 targeting prodrug triggers innate sensing to overcome checkpoint blockade resistance. Nat Commun 10(1):3251 |
| abstractText | 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 beta-lapachone triggers tumor-selective innate sensing leading to T cell-dependent tumor control. beta-Lapachone is catalyzed and bioactivated by NQO1 to generate ROS in NQO1(high) tumor cells triggering oxidative stress and release of the damage signals for innate sensing. beta-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. |
