Abstract

Unfolded protein response (UPR) is a central stress response pathway that is hijacked by tumor cells for their survival. Here, we find that IRE1alpha signaling, one of the canonical UPR arms, is increased in prostate cancer (PCa) patient tumors. Genetic or small molecule inhibition of IRE1alpha in syngeneic mouse PCa models and an orthotopic model decreases tumor growth. IRE1alpha 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 IRE1alpha in cancer cells reduces tumor-associated macrophage abundance. Consistently, the small molecule IRE1alpha inhibitor MKC8866, currently in clinical trials, reprograms the TME and enhances anti-PD-1 therapy. Our findings show that IRE1alpha signaling not only promotes cancer cell growth and survival but also interferes with anti-tumor immunity in the TME. Thus, targeting IRE1alpha can be a promising approach for improving anti-PD-1 immunotherapy in PCa.