Targeting the unfolded protein response in cancer: mechanisms, small-molecule inhibitors, and translational challenges

Abstract

Endoplasmic reticulum (ER) stress, triggered by the accumulation of misfolded proteins, activates the unfolded protein response (UPR) to restore protein homeostasis. Dysregulated ER stress responses have emerged as critical modulators of cancer progression and immune escape, influencing the initiation, development and maintenance of antitumor immunity. The UPR is mediated by three principal sensors—PERK, IRE1α, and ATF6—each operating at distinct regulatory levels to coordinate translational reprogramming, RNA processing, and transcriptional reprogramming. Through these mechanisms, ER stress promotes malignant progression, tumor growth, and metastasis, while excessive activation can instead trigger cell death. Given this context-dependent duality, pharmacological targeting of the UPR has emerged as a promising anticancer strategy. For instance, IRE1α inhibitors block XBP1 splicing and RIDD-mediated immune escape, PERK inhibitors and ISR modulators reverse chemoresistance, ATF6-targeted strategies modulate ATF6-dependent tumor growth and treatment responses, and chemical chaperones exhibit both cytoprotective and antitumor effects depending on tumor context. This review integrates recent mechanistic insights into UPR-driven tumor progression, including pathway crosstalk, immune regulation, and immunotherapy resistance, with advances in small-molecule inhibitors, while critically evaluating their therapeutic potential and translational challenges in cancer treatment.