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

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Cell. 2024 Oct 14;. doi: 10.1016/j.cell.2024.09.032

IRE1α silences dsRNA to prevent taxane-induced pyroptosis in triple-negative breast cancer. Wang (Meng) Lab

Xu L, Peng F, Luo Q, Ding Y, Yuan F, Zheng L, He W, Zhang SS, Fu X, Liu J, Mutlu AS, Wang S, Nehring RB, Li X, Tang Q, Li C, Lv X, Dobrolecki LE, Zhang W, Han D, Zhao N, Jaehnig E, Wang J, Wu W, Graham DA, Li Y, Chen R, Peng W, Chen Y, Catic A, Zhang Z, Zhang B, Mustoe AM, Koong AC, Miles G, Lewis MT, Wang MC, Rosenberg SM, O'Malley BW, Westbrook TF, Xu H, Zhang XH, Osborne CK, Li JB, Ellis MJ, Rimawi MF, Rosen JM, Chen X

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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-L1 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.

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

Abstract

PMID: 39419025 [PubMed - indexed for MEDLINE]

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