Ferroptosis in immune cells: Implications for tumor immunity and cancer therapy Original paper

What was reviewed?

This paper reviewed how ferroptosis, an iron-dependent and lipid peroxidation–driven form of regulated cell death, intersects with anti-tumor immunity and cancer therapy. The authors centered the discussion on the core biochemical “decision points” that govern ferroptosis sensitivity, including cystine import through system Xc− and downstream glutathione–GPX4 antioxidant defense, iron handling that feeds reactive oxygen species generation, and lipid metabolism features that determine how easily membranes undergo peroxidation. The review then connected these pathways to immune behavior in the tumor microenvironment, emphasizing that ferroptosis in tumor cells can be immunogenic, while ferroptosis within immune cells can cripple immune surveillance and treatment responses.

Who was reviewed?

The review covered evidence across innate and adaptive immune compartments relevant to cancer immunity, including macrophages, dendritic cells, neutrophils, T cells, and B cells, primarily in tumor contexts and immunotherapy settings. It also integrated mechanistic findings from preclinical cancer models and immunology studies where ferroptosis was induced, blocked, or genetically modified to test immune consequences. A small but relevant metabolic thread included discussion that microbial-derived metabolites can inhibit ferroptosis and thereby support colorectal cancer progression, positioning the microbiome as a potential upstream modifier of ferroptosis tone in tumors.

What were the most important findings?

The review’s most clinically relevant message is that ferroptosis has “two faces” in cancer immunity. When tumor cells undergo ferroptosis, they can release danger signals that stimulate innate sensing and support antigen presentation, creating conditions that favor adaptive immune activation and better responses to immunotherapy. In contrast, ferroptosis occurring in immune cells undermines defense: impaired dendritic-cell maturation and antigen presentation can blunt T-cell priming, lipid peroxidation pressure can reduce CD8 T-cell effector fitness, and neutrophil ferroptosis can contribute to immune suppression in the tumor microenvironment. The paper also highlighted practical molecular levers: the system Xc−–GSH–GPX4 axis and iron-driven oxidative chemistry remain dominant control points, while lipid composition regulators such as ACSL4 shape sensitivity by enriching oxidizable polyunsaturated phospholipids. For microbiome-aware clinicians, the notable “MMA-style” signal is indirect but actionable: gut microbial metabolites were described as ferroptosis inhibitors linked to colon cancer progression, suggesting that metabolite exposure may shift tumors toward ferroptosis resistance and immune escape even without changing classic immune checkpoints.

What are the greatest implications of this review?

Clinically, the review supports a combined-strategy mindset: induce ferroptosis in cancer cells to increase tumor immunogenicity, while simultaneously protecting key immune subsets from ferroptotic damage so therapy does not sabotage immune function. This framing helps explain mixed outcomes seen with oxidative or iron-targeting approaches and argues for more selective delivery, biomarker-driven patient selection, and rational pairing with immune checkpoint inhibitors. It also implies that “ferroptosis resistance” is not only a tumor-intrinsic problem; it is a microenvironmental phenotype shaped by immune polarization, nutrient availability, lipid exposure, and potentially microbiome-derived metabolites. For translational pipelines, the practical takeaway is that ferroptosis modulation should be evaluated with immune readouts (antigen presentation quality, CD8 function, suppressive myeloid activity), not only tumor cell death.