Ferroptosis and cancer: when iron turns against tumors

Background: Ferroptosis is an iron-dependent form of regulated necrosis driven by unchecked lipid peroxidation. Its relevance to cancer biology has become increasingly evident. Our long-standing ferric nitrilotriacetate (Fe-NTA) rat model exemplifies how chronic Fenton chemistry induces DNA damage, genomic instability, and selection of ferroptosis-resistant malignant clones, underscoring the central role of iron in carcinogenesis. Recent Advances: Cancer cells acquire multiple adaptations to maintain iron addiction while escaping ferroptotic pressure, including reinforcement of the xCT–CD44v axis, GPX4 and FSP1 activities, NRF2-mediated antioxidant programs, and mitochondrial remodeling. Ferroptosis can also act as an immunogenic cell death modality by releasing oxidized phospholipids and DAMPs that activate dendritic cells and CD8⁺ T cells, a process termed immunoferroptosis. Low-temperature plasma (LTP) has emerged as a unique modality capable of producing reactive oxygen and nitrogen species to selectively trigger ferroptosis in iron-loaded cancer cells while sparing normal tissues. Diagnostic and Genetic Context: HNE-modified proteins currently serve as robust markers of lipid peroxidation in FFPE samples, whereas visualization of catalytic Fe(II)—the executer of ferroptosis—requires frozen tissues or live-cell imaging. Cancer-prone hereditary syndromes such as BRCA1/2 deficiency and Fanconi anemia exhibit ferroptosis resistance, linking defective genome maintenance to impaired ferroptotic signaling. Outlook: Ferroptosis functions both as an intrinsic tumor-suppressive mechanism and a tractable therapeutic vulnerability. Harnessing ferroptosis offers a promising strategy for targeting iron-addicted cancers.