Work

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

Year: 2026

Type: article

Abstract: 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.

Source: Frontiers in Immunology

DOI: 10.3389/fimmu.2025.1726210