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Metabolic reprograming mediated by tumor cell-intrinsic type I IFN signaling is required for CD47-SIRPα blockade efficacy

Author

Listed:
  • Hang Zhou

    (Chinese Academy of Sciences)

  • Wenjun Wang

    (Chinese Academy of Sciences)

  • Hairong Xu

    (Chinese Academy of Sciences)

  • Yong Liang

    (University of the Chinese Academy of Sciences)

  • Jiyu Ding

    (Chinese Academy of Sciences
    University of the Chinese Academy of Sciences)

  • Mengjie Lv

    (Chinese Academy of Sciences)

  • Boyang Ren

    (Chinese Academy of Sciences)

  • Hua Peng

    (Chinese Academy of Sciences)

  • Yang-Xin Fu

    (Tsinghua University)

  • Mingzhao Zhu

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of the Chinese Academy of Sciences)

Abstract

Type I interferons have been well recognized for their roles in various types of immune cells during tumor immunotherapy. However, their direct effects on tumor cells are less understood. Oxidative phosphorylation is typically latent in tumor cells. Whether oxidative phosphorylation can be targeted for immunotherapy remains unclear. Here, we find that tumor cell responsiveness to type I, but not type II interferons, is essential for CD47-SIRPα blockade immunotherapy in female mice. Mechanistically, type I interferons directly reprogram tumor cell metabolism by activating oxidative phosphorylation for ATP production in an ISG15-dependent manner. ATP extracellular release is also promoted by type I interferons due to enhanced secretory autophagy. Functionally, tumor cells with genetic deficiency in oxidative phosphorylation or autophagy are resistant to CD47-SIRPα blockade. ATP released upon CD47-SIRPα blockade is required for antitumor T cell response induction via P2X7 receptor-mediated dendritic cell activation. Based on this mechanism, combinations with inhibitors of ATP-degrading ectoenzymes, CD39 and CD73, are designed and show synergistic antitumor effects with CD47-SIRPα blockade. Together, these data reveal an important role of type I interferons on tumor cell metabolic reprograming for tumor immunotherapy and provide rational strategies harnessing this mechanism for enhanced efficacy of CD47-SIRPα blockade.

Suggested Citation

  • Hang Zhou & Wenjun Wang & Hairong Xu & Yong Liang & Jiyu Ding & Mengjie Lv & Boyang Ren & Hua Peng & Yang-Xin Fu & Mingzhao Zhu, 2024. "Metabolic reprograming mediated by tumor cell-intrinsic type I IFN signaling is required for CD47-SIRPα blockade efficacy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50136-z
    DOI: 10.1038/s41467-024-50136-z
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