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Abstract Unfolded protein response (UPR) is a central stress response pathway in normal cells that is hijacked by tumor cells for their survival. However, how activation of UPR in cancer cells shapes the tumor microenvironment (TME) remain largely unexplored. Here, we investigated the role of IRE1α-XBP1s pathway on modulation of TME dynamics in prostate cancer (PCa). We found that IRE1α is increased in PCa patients and genetic or pharmacological inhibition of IRE1α signaling in the immunocompetent syngeneic mouse PCa model dramatically reduced tumor growth. Multiomics analysis of tumor samples upon IRE1α deletion in cancer cells showed significantly potentiated interferon (IFN) response and activation of immune system related pathways in the TME. Single-cell RNA sequencing (scRNA-seq) analysis revealed that the abundance of immunosuppressive cells, such as tumor-associated macrophages (TAMs) and T regulatory cells were markedly reduced in the IRE1α deficient tumors. Analysis of differentially expressed genes in the annotated cell types in the TME demonstrated that expression signatures associated with IFN responses were significantly enriched in TAMs, cancer cells, and dendritic cells. In addition, a novel scRNA-seq derived TAM gene signature is strongly associated with poor PCa survival. Furthermore, IRE1α inhibition by the small molecule MKC8866 (ORIN1001) that is in clinical trials significantly enhanced anti-PD-1 checkpoint inhibitor therapy in mice. Our findings indicate that IRE1α not only promotes cancer cell growth and survival, but it also strongly inhibits anti-tumor immunity in the PCa TME. Citation Format: Bilal Unal, Omer Faruk Kuzu, Yang Jin, Daniel Camilo Hurtado, Marieke Lydia Kuijjer, Mads Daugaard, Htoo Zarni Oo, John B. Patterson, Fahri Saatcioglu. Targeting IRE1α alleviates the immunosuppressive tumor microenvironment in prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5362.
Unal et al. (Fri,) studied this question.