IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v10y2019i1d10.1038_s41467-019-11238-1.html
   My bibliography  Save this article

NQO1 targeting prodrug triggers innate sensing to overcome checkpoint blockade resistance

Author

Listed:
  • Xiaoguang Li

    (University of Texas Southwestern Medical Center
    Shanghai Jiao Tong University School of Medicine)

  • Zhida Liu

    (University of Texas Southwestern Medical Center)

  • Anli Zhang

    (University of Texas Southwestern Medical Center)

  • Chuanhui Han

    (University of Texas Southwestern Medical Center)

  • Aijun Shen

    (University of Texas Southwestern Medical Center)

  • Lingxiang Jiang

    (Indiana University School of Medicine)

  • David A. Boothman

    (Indiana University School of Medicine)

  • Jian Qiao

    (University of Texas Southwestern Medical Center)

  • Yang Wang

    (University of Texas Southwestern Medical Center)

  • Xiumei Huang

    (Indiana University School of Medicine)

  • Yang-Xin Fu

    (University of Texas Southwestern Medical Center)

Abstract

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 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.

Suggested Citation

  • Xiaoguang Li & Zhida Liu & Anli Zhang & Chuanhui Han & Aijun Shen & Lingxiang Jiang & David A. Boothman & Jian Qiao & Yang Wang & Xiumei Huang & Yang-Xin Fu, 2019. "NQO1 targeting prodrug triggers innate sensing to overcome checkpoint blockade resistance," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11238-1
    DOI: 10.1038/s41467-019-11238-1
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-019-11238-1
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-019-11238-1?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Xuan Wang & Yingqi Liu & Chencheng Xue & Yan Hu & Yuanyuan Zhao & Kaiyong Cai & Menghuan Li & Zhong Luo, 2022. "A protein-based cGAS-STING nanoagonist enhances T cell-mediated anti-tumor immune responses," Nature Communications, Nature, vol. 13(1), pages 1-22, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11238-1. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.