Ferroptosis in breast cancer: From adipocyte-immune-iron regulation to therapeutic application.

BACKGROUND: Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a potential therapeutic vulnerability in breast cancer. However, increasing evidence indicates that ferroptosis sensitivity is not solely determined by tumour-intrinsic factors, but is dynamically regulated by the tumour microenvironment (TME), particularly through interactions among adipocytes, immune cells and iron metabolism.

MAIN BODY: Recent studies provide mechanistic evidence for this context dependence. Adipocyte-derived monounsaturated fatty acids such as oleic acid suppress lipid peroxidation and increase resistance to ferroptosis induction in triple-negative breast cancer, whereas ACSL4-driven polyunsaturated phospholipid remodelling enhances ferroptosis susceptibility. In parallel, CD8+ T-cell-derived interferon-γ promotes ferroptosis by suppressing SLC7A11-mediated cystine uptake, while tumour-associated macrophages buffer oxidative stress through iron sequestration and glutathione-dependent antioxidant programs. These opposing forces indicate that ferroptosis is governed by a coordinated adipocyte-immune-iron regulatory network rather than a single pathway. Unlike previous reviews focused mainly on tumour-intrinsic mechanisms or general TME effects, this review integrates adipocyte-derived lipid metabolism, immune-mediated redox regulation, iron handling and spatial heterogeneity into a unified 'ferroptosis ecosystem' framework. Based on this concept, we propose eco-ferrotherapy, a translational strategy aimed at simultaneously targeting tumour-intrinsic pathways and microenvironmental buffering systems. This framework may support subtype-specific therapeutic prioritisation, biomarker-guided patient stratification and rational combination strategies involving immunotherapy and nanomedicine.

CONCLUSION: Ferroptosis in breast cancer should be understood as an ecosystem-level vulnerability shaped by metabolic, immune and spatial factors. Defining and therapeutically targeting this ferroptosis ecosystem provides a conceptual and translational roadmap for improving precision treatment strategies.