PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis

Nat Cell Biol. 2020 Oct;22(10):1264-1275. doi: 10.1038/s41556-020-0575-z. Epub 2020 Sep 14.


Although pyroptosis is critical for macrophages against pathogen infection, its role and mechanism in cancer cells remains unclear. PD-L1 has been detected in the nucleus, with unknown function. Here we show that PD-L1 switches TNFα-induced apoptosis to pyroptosis in cancer cells, resulting in tumour necrosis. Under hypoxia, p-Stat3 physically interacts with PD-L1 and facilitates its nuclear translocation, enhancing the transcription of the gasdermin C (GSDMC) gene. GSDMC is specifically cleaved by caspase-8 with TNFα treatment, generating a GSDMC N-terminal domain that forms pores on the cell membrane and induces pyroptosis. Nuclear PD-L1, caspase-8 and GSDMC are required for macrophage-derived TNFα-induced tumour necrosis in vivo. Moreover, high expression of GSDMC correlates with poor survival. Antibiotic chemotherapy drugs induce pyroptosis in breast cancer. These findings identify a non-immune checkpoint function of PD-L1 and provide an unexpected concept that GSDMC/caspase-8 mediates a non-canonical pyroptosis pathway in cancer cells, causing tumour necrosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis*
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / metabolism*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Cell Proliferation
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Hypoxia / physiopathology
  • Inflammasomes
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Necrosis
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Pyroptosis*
  • Tumor Cells, Cultured
  • Tumor-Associated Macrophages
  • Xenograft Model Antitumor Assays


  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human
  • DNA-Binding Proteins
  • GSDMC protein, human
  • Inflammasomes