Remodelling the tumour microenvironment and beyond: ERO1A as a multifaceted regulator and emerging therapeutic target in cancer

Abstract

Background: Endoplasmic reticulum oxidoreductase 1α (ERO1A) is the core engine of oxidative protein folding in the endoplasmic reticulum (ER), playing a central role in maintaining ER redox homeostasis and modulating the unfolded protein response (UPR). Its aberrant overexpression in multiple solid tumors has established ERO1A as a critical regulator of tumor progression, microenvironment remodeling, and therapy resistance, positioning it as an emerging therapeutic target in precision oncology.

Main body: This review systematically synthesizes the structural biology, catalytic mechanisms, and regulatory networks of ERO1A, encompassing transcriptional control, post-translational modifications, and compensatory alternative oxidases. We detail the multidimensional oncogenic functions of ERO1A, including intracellular promotion of proliferation, apoptosis resistance, migration, invasion, and epithelial-mesenchymal transition, as well as extracellular remodeling of the tumor microenvironment via VEGF-driven angiogenesis, PD-L1-mediated immune evasion, metabolic reprogramming, and induction of CD8⁺ T cell exhaustion and recruitment of immunosuppressive cells. The clinical relevance of ERO1A as an independent prognostic biomarker and its association with chemotherapy and immune checkpoint inhibitor resistance are critically evaluated. Current therapeutic strategies targeting ERO1A are classified into FAD-competitive inhibitors, non-competitive inhibitors, allosteric inhibitors, and emerging PROTAC degraders, with discussion of their mechanisms, selectivity, and translational hurdles.

Conclusion: ERO1A represents a promising yet challenging therapeutic node that connects ER stress adaptation with tumor pathogenesis. Overcoming the limitations of current inhibitors—particularly poor isoform selectivity, off-target effects, and pharmacokinetic deficiencies-through structure-guided optimization, allosteric modulation, or protein degradation technologies will be essential for clinical translation. Future efforts should focus on biomarker-driven patient stratification and rational combination with immunotherapies or conventional chemotherapies to maximize therapeutic benefit.

Keywords

ER stress / ERO1A / oxidative folding / targeted therapy / TME

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2026 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.