Fig. 1: Mechanisms of unfolded protein response (UPR) pathways in determining cell fate under tumor microenvironment (TME) stress.

Multiple stress conditions within the TME lead to the accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER), triggering ER stress (ERS). This activates three key UPR sensors located on the ER membrane: PERK, IRE1α, and ATF6. The PERK–eIF2α–ATF4 axis primarily induces the expression of the transcription factor CHOP (C/EBP homologous protein), which serves as a central mediator of apoptosis and pyroptosis while also modulating genes involved in ferroptosis. Simultaneously, the IRE1α–XBP1s axis activates adaptive responses through metabolic reprogramming, such as enhanced lipogenesis, and protective autophagy to alleviate cellular stress. The ATF6 pathway contributes to cellular adaptation by upregulating ER chaperone proteins including GRP78 and participates in CHOP-mediated apoptotic signaling. Integration of these signaling cascades, particularly through the molecular hub CHOP, determines the ultimate cellular fate: promoting survival under mild or transient stress conditions, or driving cell death through diverse programmed cell death modalities under severe or prolonged stress. CHOP thus functions as a critical molecular switch balancing pro-survival and pro-death outcomes in response to proteotoxic stress. Created with BioRender.com.