Ferroptosis and tumor microenvironment: orchestrating therapy resistance, immune evasion, and metastatic events

Ferroptosis, an iron-dependent form of regulated cell death characterized by accumulation of lethal lipid peroxides, has emerged as a critical mechanism in cancer biology with significant implications for therapy and metastasis. This distinct mode of cell death is orchestrated through multiple molecular pathways, including the system Xc⁻/glutathione (GSH) /glutathione peroxidase 4 (GPX4) axis, iron metabolism dysregulation via transferrin receptor 1 (TFR1) and ferritin, and lipid remodeling through acyl-CoA synthetase long-chain family member 4 (ACSL4)-mediated incorporation of polyunsaturated fatty acids into membrane phospholipids. Unlike apoptosis, ferroptosis represents a unique vulnerability in cancer cells due to their elevated iron dependency, making it an attractive therapeutic target. However, the complex interplay between ferroptosis and the tumor microenvironment (TME) creates a double-edged sword that can either suppress or promote tumor progression. Recent evidence demonstrates that distinct cell populations within the TME exhibit differential sensitivities to ferroptosis, with profound consequences for tumor evolution. Mechanistically, cancer-associated fibroblasts activate the TGF-β/SMAD3/ATF4 signaling axis to upregulate sulfur transfer pathways, secreting cysteine that supports tumor cell GSH synthesis and GPX4 activity, thereby conferring ferroptosis resistance. This metabolic cross-feeding exemplifies how stromal cells create a protective niche that sustains tumor survival under oxidative stress. Additionally, exosome-mediated communication within the TME plays a pivotal role in regulating ferroptosis to facilitate metastasis, immune escape, and drug resistance. Studies have also examined how ferroptosis influences epithelial-mesenchymal transition and metastatic dissemination, while addressing the paradoxical role of ferroptosis in both promoting anti-tumor immunity and potentially suppressing immune responses depending on TME context. This review explores the multifaceted crosstalk between ferroptosis and various TME components, including cancer-associated fibroblasts, immune cells, stromal cells, and extracellular matrix elements. Moreover, ferroptosis-driven mechanisms underlying resistance to chemotherapy, radiotherapy, targeted therapies, and immunotherapy are discussed along the emerging therapeutic strategies that leverage ferroptosis induction to effectively target therapy-resistant and metastatic tumors.