IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v619y2023i7970d10.1038_s41586-023-06256-5.html
   My bibliography  Save this article

Reprogramming tumour-associated macrophages to outcompete cancer cells

Author

Listed:
  • Xian Zhang

    (Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center)

  • Shun Li

    (Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center)

  • Isha Malik

    (Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center)

  • Mytrang H. Do

    (Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
    Weill Cornell Graduate School of Medical Sciences, Cornell University)

  • Liangliang Ji

    (Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center)

  • Chun Chou

    (Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center)

  • Wei Shi

    (Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center)

  • Kristelle J. Capistrano

    (Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center)

  • Jing Zhang

    (Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center)

  • Ting-Wei Hsu

    (Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
    Cornell University)

  • Briana G. Nixon

    (Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
    Weill Cornell Graduate School of Medical Sciences, Cornell University)

  • Ke Xu

    (Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
    Weill Cornell Graduate School of Medical Sciences, Cornell University
    META Pharmaceuticals)

  • Xinxin Wang

    (Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
    Weill Cornell Graduate School of Medical Sciences, Cornell University)

  • Andrea Ballabio

    (Telethon Institute of Genetics and Medicine (TIGEM)
    Federico II University
    Baylor College of Medicine
    Texas Children’s Hospital)

  • Laura S. Schmidt

    (National Cancer Institute
    Frederick National Laboratory for Cancer Research)

  • W. Marston Linehan

    (National Cancer Institute)

  • Ming O. Li

    (Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
    Weill Cornell Graduate School of Medical Sciences, Cornell University)

Abstract

In metazoan organisms, cell competition acts as a quality control mechanism to eliminate unfit cells in favour of their more robust neighbours1,2. This mechanism has the potential to be maladapted, promoting the selection of aggressive cancer cells3–6. Tumours are metabolically active and are populated by stroma cells7,8, but how environmental factors affect cancer cell competition remains largely unknown. Here we show that tumour-associated macrophages (TAMs) can be dietarily or genetically reprogrammed to outcompete MYC-overexpressing cancer cells. In a mouse model of breast cancer, MYC overexpression resulted in an mTORC1-dependent ‘winner’ cancer cell state. A low-protein diet inhibited mTORC1 signalling in cancer cells and reduced tumour growth, owing unexpectedly to activation of the transcription factors TFEB and TFE3 and mTORC1 in TAMs. Diet-derived cytosolic amino acids are sensed by Rag GTPases through the GTPase-activating proteins GATOR1 and FLCN to control Rag GTPase effectors including TFEB and TFE39–14. Depletion of GATOR1 in TAMs suppressed the activation of TFEB, TFE3 and mTORC1 under the low-protein diet condition, causing accelerated tumour growth; conversely, depletion of FLCN or Rag GTPases in TAMs activated TFEB, TFE3 and mTORC1 under the normal protein diet condition, causing decelerated tumour growth. Furthermore, mTORC1 hyperactivation in TAMs and cancer cells and their competitive fitness were dependent on the endolysosomal engulfment regulator PIKfyve. Thus, noncanonical engulfment-mediated Rag GTPase-independent mTORC1 signalling in TAMs controls competition between TAMs and cancer cells, which defines a novel innate immune tumour suppression pathway that could be targeted for cancer therapy.

Suggested Citation

  • Xian Zhang & Shun Li & Isha Malik & Mytrang H. Do & Liangliang Ji & Chun Chou & Wei Shi & Kristelle J. Capistrano & Jing Zhang & Ting-Wei Hsu & Briana G. Nixon & Ke Xu & Xinxin Wang & Andrea Ballabio , 2023. "Reprogramming tumour-associated macrophages to outcompete cancer cells," Nature, Nature, vol. 619(7970), pages 616-623, July.
  • Handle: RePEc:nat:nature:v:619:y:2023:i:7970:d:10.1038_s41586-023-06256-5
    DOI: 10.1038/s41586-023-06256-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-023-06256-5
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.

    File URL: https://libkey.io/10.1038/s41586-023-06256-5?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
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

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


    Cited by:

    1. Weiqi Zhang & Yinghua Zeng & Qiuqun Xiao & Yuanyuan Wu & Jiale Liu & Haocheng Wang & Yuting Luo & Jie Zhan & Ning Liao & Yanbin Cai, 2024. "An in-situ peptide-antibody self-assembly to block CD47 and CD24 signaling enhances macrophage-mediated phagocytosis and anti-tumor immune responses," Nature Communications, Nature, vol. 15(1), pages 1-19, 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:nature:v:619:y:2023:i:7970:d:10.1038_s41586-023-06256-5. 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.