Several poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are approved by FDA to treat cancer with BRCA mutations. BRCA mutations are considered to fuel a PARPi killing effect by inducing apoptosis. However, resistance to PARPi is frequently observed in the clinic due to an incomplete understanding on the molecular basis of PARPi function and a lack of good markers, beyond BRCA mutations, to predict response. Here, we show that gasdermin C (GSDMC) sensitized tumor cells to PARPi in vitro and in immunocompetent mice and caused durable tumor regression in an immune-dependent manner. A high expression level of GSDMC predicted better response to PARPi treatment in patients with triple-negative breast cancer (TNBC). PARPi treatment triggered GSDMC/caspase-8–mediated cancer cell pyroptosis (CCP) that enhanced PARPi killing of tumor cells. GSDMC-mediated CCP increased memory CD8⁺ T cell population in lymph node (LN), spleen, and tumor and, thus, promoted cytotoxic CD8⁺ T cell infiltration in the tumor microenvironment. T cell–derived granzyme B (GZMB) activated caspase-6, which subsequently cleaved GSDMC to induce pyroptosis. Interestingly, IFN-γ induced GSDMC expression, which, in turn, enhanced the cytotoxicity of PARPi and T cells. Importantly, GSDMC promoted tumor clearance independent of BRCA deficiency in multiple cancer types with PARPi treatment. This study identifies a general marker and target for PARPi therapy and offers insights into the mechanism of PARPi function.

中文翻译：

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Gasdermin C 在癌症模型中使肿瘤细胞对 PARP 抑制剂治疗敏感

FDA 批准多种聚 (ADP-核糖) 聚合酶 (PARP) 抑制剂 (PARPi) 用于治疗具有 BRCA 突变的癌症。BRCA 突变被认为通过诱导细胞凋亡来增强 PARPi 杀伤作用。然而，由于对 PARPi 功能的分子基础了解不完全，并且除了 BRCA 突变之外，缺乏良好的标记物来预测反应，因此临床上经常观察到对 PARPi 的耐药性。在这里，我们表明，gasdermin C (GSDMC) 在体外和免疫功能正常的小鼠中使肿瘤细胞对 PARPi 敏感，并以免疫依赖性方式引起持久的肿瘤消退。GSDMC 的高表达水平预示着三阴性乳腺癌 (TNBC) 患者对 PARPi 治疗的更好反应。PARPi 治疗触发 GSDMC/caspase-8 介导的癌细胞焦亡 (CCP)，从而增强 PARPi 对肿瘤细胞的杀伤作用。GSDMC 介导的 CCP 增加了淋巴结 (LN)、脾脏和肿瘤中的记忆 CD8 ⁺ T 细胞数量，从而促进了肿瘤微环境中的细胞毒性 CD8 ^{+ T 细胞浸润。}T 细胞衍生的颗粒酶 B (GZMB) 激活 caspase-6，随后裂解 GSDMC 以诱导细胞焦亡。有趣的是，IFN-γ 诱导 GSDMC 表达，进而增强 PARPi 和 T 细胞的细胞毒性。重要的是，GSDMC 通过 PARPi 治疗促进肿瘤清除，而不受多种癌症类型中 BRCA 缺陷的影响。这项研究确定了 PARPi 治疗的一般标志物和靶点，并提供了对 PARPi 功能机制的见解。