Abstract
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. Its molecular network involves CHOP-mediated apoptotic imbalance, NLRP3 inflammasome-activated pyroptosis, the ATF4-CHAC1 axis-driven ferroptosis, and the dual roles of autophagy (protective or pro-death). Oxidative stress further amplifies the biological functions of this network. The ERS-Death Axis exhibits significant heterogeneity across different tumors. Therapeutic strategies targeting this axis have demonstrated clear potential, including specific modulation of core UPR molecules, pathway activation by natural compounds, synergistic combinations with immune checkpoint inhibitors and metabolic interventions, and enhanced targeting and efficacy through nanodelivery systems. However, clinical translation faces key challenges such as tumor heterogeneity, drug delivery efficiency, and complex resistance mechanisms. In-depth elucidation of the tumor-specific mechanisms underlying the ERS-Death Axis will provide crucial theoretical support for overcoming bottlenecks in cancer therapy and optimizing combination treatment regimens, propelling this axis to become a core target for precision oncology.