Figure 2.

Crosstalk between ERS and TME. Uncontrolled tumor growth generates a hostile TME, characterized by hypoxia, nutritional deficiencies, and localized acidosis, which increase the accumulation of unfolded/misfolded proteins on the ER (partly mediated by EV) and consequently ERS. Therapeutic modalities, such as chemotherapy, radiation, and immunotherapy also trigger ERS. Depending on the intensity and magnitude of ERS, the cells face two different fates through the activation of UPR. If the stressor is persistent and strong that goes beyond the adaptive capacity, UPR will mediate cell death through the induction of apoptosis or autophagy. If the ERS is tolerated, UPR signaling will lead to tumor proliferation, metastasis, and treatment resistance, which in turn aggravate the hostility of the TME. ER, endoplasmic reticulum; ERS, endoplasmic reticulum stress; EV, extracellular vesicle; ROS, reactive oxygen species; TME, tumor microenvironment; and UPR, unfolded protein response.