Unfolded protein response (UPR) is a central stress response pathway that is hijacked by tumor cells for their survival. Here, we find that IRE1α signaling, one of the canonical UPR arms, is increased in prostate cancer (PCa) patient tumors. Genetic or small molecule inhibition of IRE1α in syngeneic mouse PCa models and an orthotopic model decreases tumor growth. IRE1α ablation in cancer cells potentiates interferon responses and activates immune system related pathways in the tumor microenvironment (TME). Single-cell RNA-sequencing analysis reveals that targeting IRE1α in cancer cells reduces tumor-associated macrophage abundance. Consistently, the small molecule IRE1α inhibitor MKC8866, currently in clinical trials, reprograms the TME and enhances anti-PD-1 therapy. Our findings show that IRE1α signaling not only promotes cancer cell growth and survival but also interferes with anti-tumor immunity in the TME. Thus, targeting IRE1α can be a promising approach for improving anti-PD-1 immunotherapy in PCa.
Nature communications. 2024 Oct 15*** epublish ***
Bilal Unal, Omer Faruk Kuzu, Yang Jin, Daniel Osorio, Wanja Kildal, Manohar Pradhan, Sonia H Y Kung, Htoo Zarni Oo, Mads Daugaard, Mikkel Vendelbo, John B Patterson, Martin Kristian Thomsen, Marieke Lydia Kuijjer, Fahri Saatcioglu
Department of Biosciences, University of Oslo, Oslo, Norway., Center for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway., Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway., Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada., Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Aarhus, Denmark., Orinove Inc., Newbury Park, California, USA., Department of Biomedicine, Aarhus University, Aarhus, Denmark., Department of Biosciences, University of Oslo, Oslo, Norway. .