IRE1α 沉默 dsRNA 以防止三阴性乳腺癌中紫杉烷诱导的细胞焦亡。
IRE1α silences dsRNA to prevent taxane-induced pyroptosis in triple-negative breast cancer.
发表日期：2024 Oct 14
作者：
Longyong Xu, Fanglue Peng, Qin Luo, Yao Ding, Fei Yuan, Liting Zheng, Wei He, Sophie S Zhang, Xin Fu, Jin Liu, Ayse Sena Mutlu, Shuyue Wang, Ralf Bernd Nehring, Xingyu Li, Qianzi Tang, Catherine Li, Xiangdong Lv, Lacey E Dobrolecki, Weijie Zhang, Dong Han, Na Zhao, Eric Jaehnig, Jingyi Wang, Weiche Wu, Davis A Graham, Yumei Li, Rui Chen, Weiyi Peng, Yiwen Chen, Andre Catic, Zhibin Zhang, Bing Zhang, Anthony M Mustoe, Albert C Koong, George Miles, Michael T Lewis, Meng C Wang, Susan M Rosenberg, Bert W O'Malley, Thomas F Westbrook, Han Xu, Xiang H-F Zhang, C Kent Osborne, Jin Billy Li, Matthew J Ellis, Mothaffar F Rimawi, Jeffrey M Rosen, Xi Chen
来源：
CELL
摘要：
化疗通常与免疫检查点抑制剂（ICIs）联合使用，以增强免疫治疗反应。尽管化学免疫疗法在多种人类癌症中获得批准，但许多免疫冷肿瘤仍然没有反应。决定化疗免疫原性的机制尚不清楚。在这里，我们将 ER 应激传感器 IRE1α 确定为一个关键检查点，它限制紫杉烷化疗的免疫刺激作用，并阻止免疫冷三阴性乳腺癌 (TNBC) 的先天免疫识别。 IRE1α RNase 通过调节 IRE1 依赖性衰变 (RIDD) 沉默紫杉烷诱导的双链 RNA (dsRNA)，以防止 NLRP3 炎性体依赖性焦亡。 Trp53-/- TNBC 中 IRE1α 的抑制允许紫杉烷诱导 ZBP1 感知的广泛 dsRNA，进而激活 NLRP3-GSDMD 介导的细胞焦亡。因此，IRE1α RNase 抑制剂加紫杉烷可将 PD-L1 阴性、ICI 无反应的 TNBC 肿瘤转化为对 ICI 高度敏感的 PD-L1 高免疫原性肿瘤。我们揭示了 IRE1α 作为一种癌细胞防御机制，可以防止紫杉烷诱导的危险信号积累和细胞焦亡。版权所有 © 2024 Elsevier Inc. 保留所有权利。
Chemotherapy is often combined with immune checkpoint inhibitor (ICIs) to enhance immunotherapy responses. Despite the approval of chemo-immunotherapy in multiple human cancers, many immunologically cold tumors remain unresponsive. The mechanisms determining the immunogenicity of chemotherapy are elusive. Here, we identify the ER stress sensor IRE1α as a critical checkpoint that restricts the immunostimulatory effects of taxane chemotherapy and prevents the innate immune recognition of immunologically cold triple-negative breast cancer (TNBC). IRE1α RNase silences taxane-induced double-stranded RNA (dsRNA) through regulated IRE1-dependent decay (RIDD) to prevent NLRP3 inflammasome-dependent pyroptosis. Inhibition of IRE1α in Trp53-/- TNBC allows taxane to induce extensive dsRNAs that are sensed by ZBP1, which in turn activates NLRP3-GSDMD-mediated pyroptosis. Consequently, IRE1α RNase inhibitor plus taxane converts PD-L1-negative, ICI-unresponsive TNBC tumors into PD-L1high immunogenic tumors that are hyper-sensitive to ICI. We reveal IRE1α as a cancer cell defense mechanism that prevents taxane-induced danger signal accumulation and pyroptotic cell death.Copyright © 2024 Elsevier Inc. All rights reserved.