# The Role of Endoplasmic Reticulum Stress and Unfolded Protein Response in Gynecological Cancers: A Narrative Review

## TL;DR

This review explores how endoplasmic reticulum stress and the unfolded protein response contribute to gynecological cancers and how targeting these pathways could improve treatment.

## Contribution

The paper provides a comprehensive review of UPR signaling in gynecological cancers and highlights potential therapeutic strategies targeting this pathway.

## Key findings

- UPR activation correlates with aggressive cancer phenotypes and poor outcomes in ovarian, endometrial, and cervical cancers.
- GRP78/ATF6/PERK overexpression in ovarian cancer is linked to chemoresistance and worse survival.
- UPR signaling influences tumor-immune interactions, suggesting combinations with immunotherapy could be effective.

## Abstract

The unfolded protein response (UPR) mediated by IRE1/XBP1, PERK/eIF2α/ATF4, and ATF6/GRP78 governs tumor adaptation to hypoxia, nutrient deprivation, and therapy stress. In gynecologic malignancies (ovarian, endometrial, cervical), persistent endoplasmic reticulum (ER)-stress signaling underlies proliferation, invasion, immune evasion, and treatment resistance but also creates druggable liabilities. We conducted a narrative review of peer-reviewed literature indexed in MEDLINE (PubMed), Embase, Scopus, and Web of Science from inception through 13 September 2025. Search terms combined ER-stress/UPR pathways with gynecologic cancers. Eligible records included recent and high-quality preclinical, translational, and clinical studies, clinical trials, and high-quality reviews focused on UPR biology, biomarkers, or therapeutics. Data were synthesized by disease site and UPR branch. Across tumor types, UPR activation correlates with aggressive phenotypes and poorer outcomes. In epithelial ovarian cancer, GRP78/ATF6/PERK overexpression associates with inferior survival and chemoresistance, supporting their utility as biomarkers and therapeutic targets. Endometrial cancer demonstrates UPR gene-signature stratification of prognosis and immune infiltration, suggesting risk-adapted strategies. Cervical cancer leverages PERK/IRE1 signaling for therapy tolerance and dormancy. The tumor-immune interface is UPR-sensitive: CHOP and myeloid IRE1α signaling can dampen antitumor immunity, providing a rationale to pair UPR modulation with immunotherapy. Therapeutically, IRE1 RNase inhibitors (e.g., MKC-8866, B-I09), PERK/EIF2AK3 pathway modulators, protein-disulfide isomerase inhibition, and agents that trigger irrecoverable ER stress show preclinical efficacy, including synergy with platinum, poly (ADP-ribose) polymerase (PARP) inhibitors, HDAC6 blockers, and PD-1 inhibitors. Early clinical efforts investigating ER-stress-modulating combinations in platinum-resistant ovarian cancer highlight translational promise but remain preliminary. Thus, ER-stress/UPR signaling is a convergent, targetable axis in gynecologic cancers. Priorities include validating UPR-based prognostic signatures, defining context-specific vulnerabilities (e.g., genotype-informed IRE1/XBP1 dependence), and executing biomarker-driven clinical trials that combine UPR-targeted agents with standard chemotherapy, PARP inhibition, and immunotherapy to overcome resistance and improve patient outcomes.