How Cancer Cells Exploit Unfolded Protein Response Signaling for Survival, Metastasis, and Therapy Resistance
The unfolded protein response (UPR) is a homeostatic protective mechanism activated in response to endoplasmic reticulum (ER) stress. However, once co-opted by cancer cells, its function extends far beyond maintaining proteostasis and becomes an important regulator of tumor progression. This review summarizes how the three canonical UPR branches establish a persistent adaptive state under chronic ER stress. It discusses the molecular mechanisms by which UPR signaling maintains proteostasis, reprograms cellular metabolism, alleviates oxidative stress, and coordinates autophagy. Thereby it allows cancer cells to survive in hostile microenvironments. The review further examines how these adaptive programs support tumor metastasis by promoting anoikis resistance, epithelial-mesenchymal plasticity, and tumor dormancy, which also enhances resistance to chemotherapy and immunotherapy. Current evidence suggests that cancer cell survival, metastasis, and therapy resistance are not independent consequences of UPR activation, but interconnected manifestations of a unified stress adaptation strategy driven by the UPR. By clarifying how cancer cells exploit UPR signaling and its underlying mechanisms, this review aims to provide insights into potential specific therapeutic opportunities for cancer.