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

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机构： [1]1Department of Experimental Therapeutics, James P. Allison Institute, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA [2]Department of Molecular and Cellular Biology, Lester and Sue Smith Breast Center, Dun L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA [3]Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA [4]Therapeutic Innovation Center (THINC), and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA [5]Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA [6]Department of Chemistry, Rice University, Houston, TX 77005, USA [7]Department of Pathology, Xijing Hospital, Xi’an, Shaanxi 710032, China [8]Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA [9]College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China [10]Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA [11]Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA [12]Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA [13]HHMI Janelia Research Campus, Ashburn, VA 20147, USA [14]Department of Genetics, Stanford University, Stanford, CA 94305, USA

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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.

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出版当年[2023]版：

大类 | 1 区

生物学

小类 | 1 区生化与分子生物学 1 区细胞生物学

最新[2023]版：

大类 | 1 区

生物学

小类 | 1 区生化与分子生物学 1 区细胞生物学

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第一作者机构： [1]1Department of Experimental Therapeutics, James P. Allison Institute, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA

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通讯机构： [1]1Department of Experimental Therapeutics, James P. Allison Institute, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA [2]Department of Molecular and Cellular Biology, Lester and Sue Smith Breast Center, Dun L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA

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