Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer

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 and Fahri Saatcioglu ()
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Bilal Unal: University of Oslo
Omer Faruk Kuzu: University of Oslo
Yang Jin: University of Oslo
Daniel Osorio: University of Oslo
Wanja Kildal: Oslo University Hospital
Manohar Pradhan: Oslo University Hospital
Sonia H. Y. Kung: University of British Columbia
Htoo Zarni Oo: University of British Columbia
Mads Daugaard: University of British Columbia
Mikkel Vendelbo: Aarhus University Hospital
John B. Patterson: Newbury Park
Martin Kristian Thomsen: Aarhus University
Marieke Lydia Kuijjer: University of Oslo
Fahri Saatcioglu: University of Oslo

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-53039-1

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