Ferroptosis in cancer: molecular mechanisms, tumour microenvironment, therapeutic resistance, and clinical translation

Ferroptosis is a distinct form of regulated cell death driven by iron-dependent lipid peroxidation and oxidative membrane damage, and it differs fundamentally from apoptosis, necroptosis, and pyroptosis in its molecular mechanisms and execution pathways. Increasing evidence indicates that ferroptosis plays a pivotal role in cancer biology by regulating tumour initiation, progression, metastasis, therapeutic resistance, and interactions within the tumour microenvironment (TME). Dysregulation of iron metabolism, lipid peroxidation, amino acid metabolism, and antioxidant defence systems, including the System Xc⁻–GSH–GPX4, FSP1–CoQ₁₀, GCH1–BH4, and DHODH pathways, collectively determines cellular susceptibility to ferroptosis. Recent studies have further highlighted the contribution of organelle crosstalk, immune cell regulation, and stromal interactions in shaping ferroptotic responses and tumour evolution. In this review, we comprehensively summarise the molecular mechanisms underlying ferroptosis, its regulatory signalling networks, and the major milestones that have advanced the field. We further discuss the multifaceted role of ferroptosis across diverse malignancies, its influence on epithelial–mesenchymal transition, tumour invasion, metastasis, and immune modulation, and its emerging significance in overcoming resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy. In addition, we critically evaluate recent progress in ferroptosis-based therapeutic strategies, including nanomedicine, combination therapies, and translational advances, while highlighting current clinical challenges such as tumour heterogeneity, limited pharmacodynamic biomarkers, and safety concerns. Collectively, ferroptosis represents a promising therapeutic vulnerability that bridges fundamental cancer biology with precision oncology. Continued development of biomarker-guided patient stratification, targeted drug delivery systems, and rational combination strategies is expected to accelerate the clinical translation of ferroptosis-based therapies and improve outcomes for patients with refractory and treatment-resistant cancers.