PD-L1-Mediated Gasdermin C Expression Switches Apoptosis to Pyroptosis in Cancer Cells and Facilitates Tumor Necrosis

By Junwei Hou, Rongce Zhao, W. Xia, Chiung-Wen Chang, Y. You, Jung-Mao Hsu, L. Nie, Yeh Chen, Yu-Chuan Wang, Chunxiao Liu and 13 more. Nature Cell Biology, 2020

807 citations recorded by the source corpus.

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. Hou et al. show that following hypoxia PD-L1 translocates into the nucleus to enhance transcription of GSDMC, which is then cleaved and activated by caspase-8 to cause pyroptosis in cancer cells.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/86e84537138be36821f36e8d372577ca419f7cc6

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. Yan Yu
2. Weitong Gao
3. Yang Zhou
4. Xuepeng Wang

Citations in the corpus

• Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy (2022, background): “The nuclear PD-L1 family can switch TNFα-induced apoptosis into pyroptosis by upregulating GSDMC expression, leading to tumor necrosis and promoting tumor growth.(209) Under hypoxic stress, the phosphorylated form of STAT3 interacts with PD-L1 to promote nuclear translocation of PD-L1, which in turn”
• Regulatory mechanisms of PD-1/PD-L1 in cancers (2024, background): “Subsequently, p-Stat3-Y705 binds to the gasdermin C (GSDMC) promoter region, upregulating GSDMC gene expression, and then caspase-8 cleavage and activation of GSDMC, inducing pyroptosis in cells and resulting in necrosis in the hypoxic region of tumors [147].”
• Regulated cell death (RCD) in cancer: key pathways and targeted therapies (2022, background): “Some research results show that the pyroptosis caused by hypoxia in the tumor center can promote the development of tumor and reduce the survival rate of patients.(352) Chronic inflammation caused by inflammatory mediators increases the risk of tumorigenesis.”
• Pyroptosis in inflammatory diseases and cancer (2022, background): “Besides, caspase-8 can also cleave GSDMC, liberating the N-terminus of GSDMC to form pores in the cancer cell membrane [42].”
• Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research (2022, background): “Cheng Z, Li Z, Gu L, Li L, Gao Q, Zhang X, et al. Ophiopogonin B alleviates cisplatin resistance of lung cancer cells by inducing caspase-1/ GSDMD dependent pyroptosis.”