Language

English

Publication Date

12-12-2024

Journal

Cell

DOI

10.1016/j.cell.2024.09.032

PMID

39419025

PMCID

PMC11645245

PubMedCentral® Posted Date

12-12-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Chemotherapy is often combined with immune checkpoint inhibitor (ICI) 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 dsRNA through RIDD (Regulated IRE1-Dependent Decay) 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

Triple Negative Breast Neoplasms, Pyroptosis, Endoribonucleases, Humans, Taxoids, Female, RNA, Double-Stranded, Animals, Cell Line, Tumor, Mice, Protein Serine-Threonine Kinases, NLR Family, Pyrin Domain-Containing 3 Protein, Bridged-Ring Compounds, Inflammasomes, B7-H1 Antigen, Endoplasmic Reticulum Stress, Immune Checkpoint Inhibitors

Published Open-Access

yes

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