Under the conditions of protein homeostasis in normal cells, sensors of ERS, including ATF6, IRE1a and PERK are inactivated, whereas in the tumor microenvironment (TME), multiple factors such as hypoxia [18], abnormal nutrient supply [19] and ROS accumulation [20] interfere with protein folding in the ER, thereby driving ERS in cancer cells. The gene discussed is ERN1; the disease is cancer.