Endoplasmic reticulum stress in breast cancer metastasis: mechanisms and therapeutic implications

To summarize the roles of endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) in breast cancer (BC) invasion and metastasis and discuss the therapeutic potential of targeting these processes.

This review examines the molecular mechanisms linking ERS/UPR signaling to BC progression and synthesizes ERS-targeted anti-metastatic strategies reported over the past decade, including pathway inhibition, ERS hyperactivation, induction of immunogenic cell death, and combination approaches.

ERS is an adaptive response to adverse conditions within the tumor microenvironment (TME), including hypoxia and nutrient deprivation. ERS/UPR signaling can reshape tumor cell behavior and the TME to promote invasion and metastasis. Clinically, elevated ERS activity is associated with poor prognosis, shorter survival, and reduced therapeutic responsiveness. Therapeutic strategies include inhibiting pro-survival ERS pathways, hyperactivating ERS to induce tumor cell death, and exploiting ERS to trigger immunogenic cell death. However, the context-dependent and subtype-specific roles of ERS, together with potential on-target toxicity in normal tissues, complicate clinical translation.

ERS represents a therapeutically actionable vulnerability in metastatic BC. Improved patient stratification using ERS/UPR biomarkers, rational combination regimens, and tumor-selective delivery platforms may help maximize therapeutic efficacy while minimizing systemic toxicity.