Iron-fueled ferroptosis: a new axis for immunomodulation to overcome cancer drug resistance—from immune microenvironment crosstalk to therapeutic translation

Resistance to chemotherapy and targeted therapy in cancer is largely due to evasion of apoptosis, but ferroptosis—an iron-dependent form of regulated cell death driven by lipid peroxidation—offers a promising alternative, particularly in aggressive and therapy-resistant subtypes. The tumor immune microenvironment plays a central role in modulating ferroptosis susceptibility: CD8 + T cell-derived IFNγ downregulates system Xc - and upregulates ACSL4, while other immune cells such as Tregs, MDSCs, and macrophages further fine-tune ferroptosis through cytokine and redox signaling. Importantly, ferroptosis induction promotes immunogenic cell death, enhancing T cell infiltration and synergizing with immune checkpoint blockade to achieve sustained antitumor immunity. This review delineates the molecular basis of ferroptosis sensitivity in resistant cancers, explores immune-ferroptosis crosstalk, evaluates combination strategies with immunotherapy, and discusses challenges such as toxicity and patient stratification to advance clinical translation.