Cell. 2024 Oct 16. IF: 45.5
IRE1α silences dsRNA to prevent taxane-induced pyroptosis in triple-negative breast cancer.
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.
The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Baylor College of Medicine, Houston, TX, USA; Rice University, Houston, TX, USA; Xijing Hospital, Xi'an, Shaanxi, China; College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, China; University of Houston, Houston, TX, USA; HHMI Janelia Research Campus, Ashburn, VA, USA; Stanford University, Stanford, CA, USA.
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.
KEYWORDS: ER stress; IRE1α; PD-L1-negative breast cancer; dsRNA; pyroptosis
PMID: 39419025
DOI: 10.1016/j.cell.2024.09.032
Nat Rev Immunol. 2024 Oct 28. IF: 67.7
Targeting ER stress sensor restores immunogenicity of chemotherapy.
Yvonne Bordon.
Nature Reviews Immunology.
PMID: 39468370
DOI: 10.1038/s41577-024-01107-4
