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.

尽管细胞焦亡对巨噬细胞抵抗病原体感染至关重要，但其在癌细胞中的作用和机制仍不清楚。已在细胞核中检测到 PD-L1，但功能未知。在这里，我们显示 PD-L1 在癌细胞中将 TNFα 诱导的细胞凋亡转变为细胞焦亡，导致肿瘤坏死。在缺氧条件下，p-Stat3 与 PD-L1 发生物理相互作用并促进其核转位，增强gasdermin C ( GSDMC) 基因。GSDMC 在 TNFα 处理下被 caspase-8 特异性切割，产生 GSDMC N 端结构域，在细胞膜上形成孔并诱导细胞焦亡。体内巨噬细胞衍生的 TNFα 诱导的肿瘤坏死需要核 PD-L1、caspase-8 和 GSDMC。此外，GSDMC 的高表达与较差的存活率相关。抗生素化疗药物诱导乳腺癌细胞焦亡。这些发现确定了 PD-L1 的非免疫检查点功能，并提供了一个意想不到的概念，即 GSDMC/caspase-8 介导癌细胞中的非典型细胞焦亡途径，导致肿瘤坏死。