Hypoxia, oxidative stress, and impaired protein folding contribute to tumor progression and therapy resistance. Endoplasmic Reticulum Oxidoreductin 1 Alpha (ERO1α) is a key enzyme regulating redox homeostasis in the endoplasmic reticulum by reoxidizing protein disulfide isomerase, facilitating disulfide bond formation, and generating reactive oxygen species. Elevated ERO1α levels are associated with increased tumor aggressiveness, metastasis, and poor clinical outcomes. Despite growing evidence of its tumor-promoting functions, no clinically approved ERO1α inhibitors exist. This systematic review provides a comprehensive and integrative analysis of current research on ERO1α in breast cancer, emphasizing its roles in hypoxia response, angiogenesis, immune modulation, and ferroptosis resistance. We discuss mechanistic links, including VEGF-A maturation and PD-L1-mediated immune evasion, and highlight recent advances in small-molecule ERO1α inhibitors and preclinical therapeutic strategies. By consolidating molecular insights and translational considerations, this review underscores ERO1α as both a promising therapeutic target and potential prognostic marker, offering guidance for future drug development and targeted interventions in redox-dependent cancer pathways.

The endoplasmic reticulum (ER) is critical in aiding cells in ensuring that proteins are folded and processed correctly, particularly during stressful situations. ER oxidoreductin-1 alpha (ERO1α) is an enzyme that is responsible for the formation of disulfide bonds during protein folding, along with protein disulfide isomerase (PDI). This redox pathway is often highly upregulated in cancer cells, allowing tumors to survive harsh conditions such as hypoxia and nutrient deprivation. This review discusses the role of the ERO1α–PDI system in cancer development through the regulation of oxidative stress, redox homeostasis, and tumor plasticity. It further shows the therapeutic potential of interrupting the ERO1α–PDI axis, which could lead to protein misfolding; enhanced generation of reactive oxygen species (ROS); and, eventually, cancer cell death.

Resistance to cancer therapy remains a major limitation in oncology, often leading to disease progression despite an initial response to treatment. One of the key factors underlying this phenomenon is the ability of cancer cells to adapt to oxidative stress. Many anticancer therapies rely on the generation of reactive oxygen species (ROS) to induce cell death, yet tumor cells can counteract this effect by strengthening their antioxidant capacity and adjusting redox-related pathways. This review focuses on how redox homeostasis is altered in cancer and how these changes support survival under therapeutic pressure. It discusses the role of major antioxidant systems, including glutathione and thioredoxin, as well as transcriptional regulators such as NRF2, HIF-1α, and NF-κB. In addition, it highlights how ROS influence key processes in tumor progression, including proliferation, apoptosis evasion, angiogenesis, and metastasis. Therapeutic approaches aimed at disrupting redox balance are also discussed, including strategies that either increase ROS levels or interfere with antioxidant systems and endoplasmic reticulum enzymes such as ERO1α and protein disulfide isomerase. While these approaches have shown encouraging results in experimental settings, their translation into clinical use is still constrained by issues related to selectivity and the emergence of resistance. Combining redox-targeting agents with standard treatments may offer a more practical way to enhance their effectiveness and improve patient outcomes.