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Enhancing Gasdermin-induced tumor pyroptosis through preventing ESCRT-dependent cell membrane repair augments antitumor immune response

Author

Listed:
  • Zhaoting Li

    (University of Wisconsin-Madison
    University of Wisconsin-Madison
    University of Wisconsin-Madison)

  • Fanyi Mo

    (University of Wisconsin-Madison)

  • Yixin Wang

    (University of Wisconsin-Madison
    University of Wisconsin-Madison
    University of Wisconsin-Madison)

  • Wen Li

    (University of Wisconsin-Madison)

  • Yu Chen

    (University of Wisconsin-Madison
    University of Wisconsin-Madison
    University of Wisconsin-Madison)

  • Jun Liu

    (University of Wisconsin-Madison
    University of Wisconsin-Madison
    University of Wisconsin-Madison)

  • Ting-Jing Chen-Mayfield

    (University of Wisconsin-Madison)

  • Quanyin Hu

    (University of Wisconsin-Madison
    University of Wisconsin-Madison
    University of Wisconsin-Madison)

Abstract

Pore-forming Gasdermin protein-induced pyroptosis in tumor cells promotes anti-tumor immune response through the release of pro-inflammatory cytokines and immunogenic substances after cell rupture. However, endosomal sorting complexes required for transport (ESCRT) III-mediated cell membrane repair significantly diminishes the tumor cell pyroptosis by repairing and subsequently removing gasdermin pores. Here, we show that blocking calcium influx-triggered ESCRT III-dependent membrane repair through a biodegradable nanoparticle-mediated sustained release of calcium chelator (EI-NP) strongly enhances the intracellularly delivered GSDMD-induced tumor pyroptosis via a bacteria-based delivery system (VNP-GD). An injectable hydrogel and a lyophilized hydrogel-based cell patch are developed for peritumoral administration for treating primary and metastatic tumors, and implantation for treating inoperable tumors respectively. The hydrogels, functioning as the local therapeutic reservoirs, can sustainedly release VNP-GD to effectively trigger tumor pyroptosis and EI-NP to prevent the ESCRT III-induced plasma membrane repair to boost the pyroptosis effects, working synergistically to augment the anti-tumor immune response.

Suggested Citation

  • Zhaoting Li & Fanyi Mo & Yixin Wang & Wen Li & Yu Chen & Jun Liu & Ting-Jing Chen-Mayfield & Quanyin Hu, 2022. "Enhancing Gasdermin-induced tumor pyroptosis through preventing ESCRT-dependent cell membrane repair augments antitumor immune response," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34036-8
    DOI: 10.1038/s41467-022-34036-8
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