Mol Cancer. 2026 Jan 14.
Ferroptosis is a non-apoptotic form of regulated cell death driven by iron dependent lipid peroxidation. It sits at the intersection of several hallmarks of metastatic cancer, including metabolic rewiring, membrane remodeling, epithelial mesenchymal plasticity, immune editing, and adaptation to distant niches. In this review, we integrate biochemical mechanisms with single cell, spatial, and in vivo data to map how ferroptotic pressure changes as tumor cells invade, travel through vessels, extravasate, enter dormancy, and re-awaken to form overt metastases. We highlight that these dynamics are strongly shaped by organ context. Lymph and adipose rich environments buffer lipid peroxidation and favor survival. In contrast, blood circulation increases oxidative load, and brain and liver niches impose distinct constraints on redox balance, iron handling, and lipid repair. We then examine how ferroptosis interfaces with the immune system. Ferroptotic stress can increase tumor antigenicity and danger signaling and thereby promote antitumor responses. The same stress, however, can reprogram monocytes, macrophages, and neutrophils, drive neutrophil extracellular trap formation, and support lipid exchange that weakens effector T cell function. This dual behavior helps explain why ferroptosis can restrict dissemination in some settings yet fuel pro-metastatic inflammation in others. On this mechanistic background, we evaluate therapeutic strategies that aim to exploit ferroptosis related vulnerabilities. These include inhibition of cystine supply or lipid repair pathways, radiosensitization regimens that increase lipid peroxidation, diet drug combinations that rewire sulfur and lipid metabolism, and nanoplatforms that co-deliver ferroptosis triggers with photo or sonodynamic therapies. Clinically, ferroptosis programs are increasingly linked to metastatic organotropism, responses to radiotherapy and immunotherapy, and patient survival, and they are beginning to guide biomarker development and early translational trials. We also discuss practical barriers, such as niche specific resistance circuits, constraints imposed by drug delivery and toxicity, and the scarcity of robust patient level ferroptosis readouts. Methodological advances - including compartment resolved reporters, spatial lipidomics, and circulating signatures of lipid damage - may help address these gaps. Overall, viewing metastasis through the ferroptosis lens reveals actionable vulnerabilities and supports rational radio immunometabolic combinations aimed at durable control of metastatic disease.
Keywords: Epithelial–mesenchymal plasticity; Ferroptosis; Immunogenic cell death; Iron metabolism; Lipid peroxidation; Metastasis; Metastatic niche; Organotropism