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

## TL;DR

Ferroptosis, an iron-dependent cell death process, can be harnessed to combat drug-resistant cancers by interacting with the immune system and enhancing immunotherapy.

## Contribution

This review introduces ferroptosis as a novel immunomodulatory axis to overcome cancer drug resistance through immune microenvironment interactions.

## Key findings

- Ferroptosis susceptibility is modulated by immune cells like CD8+ T cells, Tregs, MDSCs, and macrophages.
- Ferroptosis induction enhances immunogenic cell death and synergizes with immune checkpoint blockade.
- Combining ferroptosis with immunotherapy faces challenges like toxicity and patient stratification.

## 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.