Ferroptosis, an iron-dependent and lipid peroxidation-driven form of regulated cell death, has emerged as a “versatile player” in oncology. It exerts a dual, context-dependent role in cancer, acting as both a potent tumor suppressor and a facilitator of tumor progression and therapeutic resistance. This review systematically delineates the core molecular regulatory networks of ferroptosis, highlighting the intricate balance between its execution mechanisms—driven by polyunsaturated fatty acid (PUFA) oxidation, iron catalysis, and mitochondrial dysfunction—and the robust endogenous defense systems, including the GSH-GPX4, FSP1/DHODH-CoQ10, and GCH1-BH4 axes. We deeply explore the dichotomous nature of ferroptosis in tumorigenesis: while classical tumor suppressors like p53 and CDKN2A harness ferroptosis to halt tumor growth, cancer cells can hijack lipid metabolic reprogramming and specific enzymes (e.g., iPLA2β) to evade cell death and promote distant metastasis. Furthermore, we dissect the multidimensional crosstalk between ferroptosis and the tumor microenvironment (TME), emphasizing its bidirectional immunoregulatory effects. Although CD8+ T cell-derived IFN-γ can sensitize tumor cells to ferroptosis and amplify anti-tumor immunity, aberrant ferroptotic activation can paradoxically foster an immunosuppressive niche. Finally, we summarize the latest translational strategies using small-molecule inducers and synergistic combination therapies, emphasizing that biomarker-guided patient stratification remains the ultimate paradigm for overcoming resistance and realizing precision ferroptosis-targeted cancer therapy.
Zhu et al. (2026) studied this question.