ABSTRACT Cellular stress evoked by immunogenic anticancer treatments engaging the unfolded protein response (UPR) can elicit inflammation with conflicting therapeutic outcomes. To define cell-autonomous mechanisms coupling the UPR to molecular mediators of inflammation, we profiled the transcriptome of cancer cells responding to immunogenic or weakly immunogenic-treatments. Bioinformatics-driven pathway analysis indicated that immunogenic treatments instigated NF-κB/AP-1-inflammatory pathways, which were abolished by the IRE1α-kinase inhibitor KIRA6. Cell-free fractions of chemotherapy and KIRA6 co-treated cancer cells were deprived of pro-inflammatory/chemoattractant factors and failed to mobilize innate immune cells. Strikingly, these potent KIRA6 anti-inflammatory effects were found to be independent of IRE1α. Generation of a KIRA6-clickable photoaffinity probe, mass spectrometry and co-immunoprecipitation analysis identified cytosolic HSP60 as a KIRA6 off-target in the NF-κB pathway. In sum, our study unravels that inflammation evoked by immunogenic treatments is curtailed by KIRA6 independently of IRE1α and further suggests great caution in interpreting the anti-inflammatory action of IRE1α chemical inhibitors.

The IRE1 Inhibitor Kira6 Curtails The Inflammatory Trait Of Immunogenic Anticancer Treatments By Targeting Hsp60 Independent Of IRE1