Fig. 3
From: Unfolding anti-tumor immunity: ER stress responses sculpt tolerogenic myeloid cells in cancer
IRE1ɑ-XBP1 is one of the arms of UPR that polarizes tumor-infiltrating myeloid cells into highly immunosuppressive populations. Over activation of IRE1ɑ-XBP1 pathway by the byproduct adduct 4-hydroxy-trans-2-nonenal (4-HNE) in the tumor microenvironment (TME) shifts tumor-infiltrating dendritic cells towards a tolerogenic phenotype that promotes cancer cell growth. IRE1ɑ-XBP1 activation upregulates lectin-type oxidized LDL receptor-1 (LOX-1) that converts high density anti-tumor neutrophils to low density immunosuppressive polymorphonuclear myeloid cells (PMN-MDSCs). IL-4 and IL-6 signals synergize with IRE1ɑ-XBP1 to enhance the ability of tumor-associated macrophages to secret Cathepsin proteases, which facilitate cancer cell invasion and metastasis