Targeting the unfolded protein response in cancer: exploiting endoplasmic reticulum stress for therapeutic intervention.

Targeting the unfolded protein response (UPR) has become an attractive cancer therapeutic approach. It takes advantage of the distinct ways tumor cells adapt to stress for their growth and survival. Due to rapid cell division, low oxygen levels, and limited nutrients, cancer cells often undergo endoplasmic reticulum (ER) stress, which activates the UPR. The UPR response is controlled by major sensors-inositol-requiring enzyme 1 (IRE1), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6), which help cancer cells adapt and avoid cell death, but provide potential targeted therapeutic strategy. Current strategies to target the UPR in cancer either block its survival-promoting pathways or push the system beyond its limits to trigger tumor cell death. Small-molecule drugs that inhibit key UPR proteins like IRE1α, PERK, and ATF6 have shown encouraging results in preclinical studies and are now being tested in clinical trials. These compounds, used alone or in combination with standard therapies, may help overcome drug resistance with fewer side effects, as normal cells do not usually face prolonged ER stress. This review explores how cancer cells exploit ER and mitochondrial stress signaling to fuel processes such as epithelial-to-mesenchymal transition (EMT), angiogenesis, cancer stem cells (CSCs), and immune system evasion. We also discuss new therapeutic approaches that target these weaknesses. Finally, we emphasize the promise of precision medicine strategies that disrupt cancer-specific stress responses, potentially offering new ways to overcome resistance and improve patient outcomes.