ER stress during cancer growth, stress-rich microenvironments, such as low pH, hypoxia, nutrition deprivation, and metabolic stress, can induce ROS formation and accumulation of misfolded proteins that lead to ER stress and UPR via activation of three signaling arms coordinated by IRE1-XBP1, PERK-eIF2a-ATF4, and ATF6. This evidence concerns the gene ATF4 and cancer.