PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis PMID: 32929201

ADC Targets in Oncology

2026-04-10

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.

Junwei Hou ¹ , Rongce Zhao ¹ ² ³ , Weiya Xia ¹ , Chiung-Wen Chang ¹ , Yun You ¹ , Jung-Mao Hsu ¹ ⁴ , Lei Nie ¹ , Yeh Chen ⁴ ⁵ , Yu-Chuan Wang ⁴ , Chunxiao Liu ¹ , Wei-Jan Wang ¹ ⁶ , Yun Wu ⁷ , Baozhen Ke ¹ , Jennifer L Hsu ¹ , Kebin Huang ¹ ⁸ , Zu Ye ¹ , Yi Yang ¹ , Xianghou Xia ¹ , Yintao Li ¹ , Chia-Wei Li ¹ , Bin Shao ¹ ⁹ , John A Tainer ¹ , Mien-Chie Hung ¹⁰ ¹¹ ¹²

Affiliations

1. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
2. Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China.
3. Department of Liver Surgery, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
4. Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan.
5. Institute of New Drug Development, China Medical University, Taichung, Taiwan.
6. Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.
7. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
8. State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin, China.
9. Key Laboratory of Carcinogenesis and Transformation Research (Ministry of Education), Department of Breast Oncology, Peking University Cancer Hospital and Institute, Beijing, China.
10. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
11. Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan. [email protected].
12. Department of Biotechnology, Asia University, Taichung, Taiwan. [email protected].

Abstract

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.