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

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.

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.

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.