Fig. 3

Effects of UPR signals on antitumor immunity. Nutrient starvation/excess or accumulation of ROS in tumor microenvironment leads to induction of ER stress in T cells and thus causes T cell exhaustion. High cholesterol levels in TME can activate PERK-eIF2α and IRE1α–XBP1 signaling in intratumoral T cells and induce the expression of PD1, which leads to the inhibition of CD8⁺ T cell antitumor immunity. Cancer cells undergoing ER stress activate PERK and IRE1α signals, which leads to upregulation of ATF4 and XBP1s. ATF4 and XBP1s directly upregulate the expression of PD-L1, triggering T cell exhaustion. Under hostile environmental condition, ER stress activates IRE1α and ATF6α and induces the transformation of HPSC into MDSCs. PERK can also induce the transformation of PMN-MDSCs into MDSCs, leading to immunosuppression. Among three UPR branches, activated PERK directly phosphorylates NRF2 and increases the expression of antioxidant genes, leading to limitation of ROS and maintenance of mitochondrial genome stability in MDSCs. This increase of mitochondrial genome stability inhibits the expression of IFN α/β and thereby suppresses T cell infiltration. Activated PERK also increases the expression of CHOP, leading to upregulation of IL-6 and thus promotes CD8⁺ T cell exhaustion. DCs are responsible for antigen processing and presentation and promote the transformation of T cells into CD8⁺T cells. ROS accumulation in DCs causes IRE1α-XBP1 activation, which drives uncontrolled lipid droplet formation and leads to the inhibition of antigen presentation of DCs. The hostile microenvironment can also activate IRE1α–XBP1 signaling and upregulate the expression of miR-23a in macrophages, leading to the increase of PD-L1 expression. Additionally, CD4⁺ T cells exploit IRE1α–XBP1 signaling to control Ca²⁺ mobilization and expression of IL4, which is necessary for the activation of CD8⁺ T cells