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

• DOI: 10.1038/s41467-024-53039-1
• Publication Date: 2024-10-15T16:02:39Z
• Authors: 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 T...; Marieke Lydia Kui...; Fahri Saatcioglu
• Keywords: Male; Science; Q; Programmed Cell Death 1 Receptor; Prostatic Neoplasms; Protein Serine-Threonine Kinases; Article; Mice, Inbred C57BL; Mice; Cell Line, Tumor; Endoribonucleases; Tumor-Associated Macrophages; Tumor Microenvironment; Unfolded Protein Response; Animals; Humans; Immunotherapy; Signal Transduction

Unfolded protein response (UPR) is a central stress pathway that hijacked by tumor cells for their survival. Here, we find IRE1α signaling, one of the canonical UPR arms, increased in prostate cancer (PCa) patient tumors. Genetic or small molecule inhibition syngeneic mouse PCa models and an orthotopic model decreases growth. ablation potentiates interferon responses activates immune system related pathways microenvironment (TME). Single-cell RNA-sequencing analysis reveals targeting reduces tumor-associated macrophage abundance. Consistently, inhibitor MKC8866, currently clinical trials, reprograms TME enhances anti-PD-1 therapy. Our findings show signaling not only promotes cell growth survival but also interferes with anti-tumor immunity TME. Thus, can be promising approach improving immunotherapy PCa.