IRE1α is a type I transmembrane protein that senses misfolded proteins in the ER. Upon activation, it undergoes dimerization and autophosphorylation, which activates its endoribonuclease (RNase) activity. This leads to the splicing of X-box binding protein 1 (XBP1) mRNA, producing the active transcription factor XBP1s, which regulates the expression of genes involved in alleviating ER stress. In addition to splicing XBP1, IRE1α also mediates a process known as regulated IRE1-dependent decay (RIDD), which selectively degrades certain mRNAs to reduce the load of new proteins entering the ER, thereby helping to restore ER homeostasis. IRE1α has been implicated in various cancers, including triple-negative breast cancer (TNBC). Its activation in cancer cells can promote tumor progression by fostering an immunosuppressive tumor microenvironment. Targeting IRE1α has shown potential in enhancing anti-tumor immunity and the effectiveness of immunotherapies. Studies indicate that inhibiting IRE1α can lead to significant tumor regression and improved survival rates in mouse models of cancer. Specifically, IRE1α loss has been associated with reduced immunosuppressive cells and increased CD8+ T cell populations in the tumor microenvironment.
中文
