美国德克萨斯大学Xi Chen研究小组发现，IRE1α通过沉默dsRNA来防止三阴性乳腺癌中紫杉类药物诱导的细胞焦亡。这一研究成果于2024年10月16日在线发表在国际学术期刊《细胞》上。

研究人员确定了内质网应激传感器IRE1α是限制紫杉类化疗免疫刺激效应的关键检查点，并防止免疫冷的三阴性乳腺癌（TNBC）被先天免疫识别。IRE1α核酸酶通过受调节的IRE1依赖性降解（RIDD）沉默紫杉类药物诱导的双链RNA（dsRNA），从而防止NLRP3炎性小体依赖的细胞焦亡。

抑制Trp53^−/− TNBC中的IRE1α允许紫杉类药物诱导大量dsRNA，这些dsRNA被ZBP1识别，进而激活NLRP3-GSDMD介导的细胞焦亡。

因此，IRE1α核酸酶抑制剂加紫杉类药物可将PD-L1阴性、对免疫检查点抑制剂（ICI）无反应的TNBC肿瘤转化为PD-L1高表达的免疫原性肿瘤，进而对ICI高度敏感。研究人员揭示了IRE1α作为癌细胞防御机制，防止紫杉类药物引发的危险信号积累和细胞焦亡。

据介绍，化疗通常与ICI联合使用，以增强免疫治疗的反应。尽管化疗联合免疫疗法已获批准用于多种人类癌症，许多免疫冷肿瘤仍对治疗无反应。化疗免疫原性的决定机制尚不清楚。

附：英文原文

Title: IRE1α silences dsRNA to prevent taxane-induced pyroptosis in triple-negative breast cancer

Author: 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

Issue&Volume: 2024-10-16

Abstract: 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.

DOI: 10.1016/j.cell.2024.09.032

Source: https://www.cell.com/cell/abstract/S0092-8674(24)01090-0