Endoplasmic reticulum stress (ERS) dynamically regulates cell fate decisions within the tumor microenvironment (TME) through the PERK, IRE1α, and ATF6 pathways of the unfolded protein response (UPR), forming an “ERS-Death Axis” interconnected with apoptosis, autophagy, pyroptosis, and ferroptosis. This evidence concerns the gene ERN1 and neoplasm.