Reshaping the Immune Tumor Microenvironment Through IRE1 Signaling

ER stress and the UPR strongly affect tumor progression in vivo and in vitro. The UPR is a major regulator of inflammation, cell death, angiogenesis, and metabolism. In addition, it can affect cancer cell immune recognition through processes that are yet not fully understood. The IRE1 branch of the UPR is so far the best-documented in its ability to control cell death or survival in tumors. An increase in IRE1 signaling has been associated with an increase in mRNA expression for key antitumor T cell markers in tumors from colorectal, glioblastoma, and cancer melanoma patients. The ability of a tumor cell to cope with environmental and intracellular stress depends on its capacity to activate appropriate adaptive pathways. As such, the endoplasmic reticulum (ER) adjusts the adaptive capacity of tumor cells by engaging the unfolded protein response (UPR). The UPR maintains the functionality of the secretory pathway, thereby allowing tumor cells to shape their microenvironment, thus likely determining the nature of the tumor immune response. Consequently, this makes the UPR very relevant in the context of cancer therapeutics. We focus here on inositol-requiring enzyme 1α (IRE1) and compile novel molecular mechanisms demonstrating that tumoral UPR controls the tumor microenvironment (TME) and the immune response, therefore opening potential novel therapeutic avenues. The ability of a tumor cell to cope with environmental and intracellular stress depends on its capacity to activate appropriate adaptive pathways. As such, the endoplasmic reticulum (ER) adjusts the adaptive capacity of tumor cells by engaging the unfolded protein response (UPR). The UPR maintains the functionality of the secretory pathway, thereby allowing tumor cells to shape their microenvironment, thus likely determining the nature of the tumor immune response. Consequently, this makes the UPR very relevant in the context of cancer therapeutics. We focus here on inositol-requiring enzyme 1α (IRE1) and compile novel molecular mechanisms demonstrating that tumoral UPR controls the tumor microenvironment (TME) and the immune response, therefore opening potential novel therapeutic avenues. the formation of new blood vessels that fuel cancer cells with oxygen and nutrients. an intracellular degradation process that takes place via the delivery of cytoplasmic entities to the lysosomes, where macromolecules are lysed and their components recycled. intracellular molecules that function as ‘eat me' signals for the immune system when exposed by or released from the cell; these promote and amplify the immune response. a highly organized organelle with diverse functions, including lipid production, calcium homeostasis, drug detoxification, and protein synthesis. The ER is equipped with the biochemical machinery to promote proper protein maturation and folding, assess protein quality, and direct defective proteins to repair or degradation processes. a pathway directing misfolded proteins in the ER for ubiquitination and proteasomal degradation. a type of cell death that triggers an immune response via the release of DAMPS. Most chemotherapies used in the clinic induce tolerogenic cancer cell death, a ‘silent' type of death that is not recognized by the immune system. the processes by which the host immune system recognizes and targets cancer cells. varying the ratio of the macronutrients in the diet to meet specific metabolic needs. the multistep process of cancer cell migration from its primary tumor site leading to colonization of remote tissues. maintenance of proper protein functioning in the cell. the mechanism of microRNA/mRNA degradation via the endoRNase activity of activated IRE1. cell contact-independent transmission of ER stress between cancer cells and from cancer cells to cells of TME. the unique environment consisting of cancer and non-cancer (stromal, immune) cells present in tumors that is characterized by hypoxia, nutrient deprivation, and reduced pH.