Ferroptosis Inhibition Blocks Tumor Growth by Restoring T-cell Function

Recent studies have implicated ferroptosis in the suppression of tumor growth in cell lines and immunodeficient mouse models. However, induction of ferroptosis in immunocompetent hosts has produced underwhelming results, suggesting a critical role for the immune system in altering outcomes to these therapies. To determine the effects of ferroptosis on the immune system, Kim, Hashimoto, and colleagues investigated how ferroptosis affects pathologically activated neutrophils-myeloid derived suppressor cells (PMN-MDSC), a cell type that negatively regulates antitumor immunity, and showed accumulation of ferroptosis-associated lipid signals (FALIS), including oxidized phosphatidylethanolamine containing arachidonic acid (PEox-AA) in intratumoral PMN-MDSCs as well as their sensitivity to death after treatment with an inducer of ferroptosis. Moreover, treatment of nonsuppressive PMNs with ferroptosis inducers stimulated their immunosuppressive activity, as indicated by a reduction in T-cell proliferation, which suggests that ferroptosis mediates the conversion of PMNs to PMN-MDSCs, with this suppressive effect being mediated by secreted factors. Moreover, genetic and pharmacologic inhibition of ferroptosis by Alox12/15 deletion or liproxstatin-1 treatment abrogated the immunosuppressive effect of tumor PMN-MDSCs in murine models and patient samples. Mechanistically, accumulation of PEox-AA and the release of oxidized phospholipids, which are major products of ferroptosis, resulted in suppression of T-cell proliferation. Additionally, evaluation of the effects of pharmacologic inhibition of ferroptosis on tumor growth showed that tumor growth was reduced in immunocompetent but not immunodeficient mice, along with an increase in functional T cells. Synergism with PD-1 blockade was also observed, resulting in tumor regression in 50% of mice. Lastly, analysis of patient data from The Cancer Genome Atlas revealed correlations between PMN-MDSC and ferroptosis expression signatures in multiple cancer types, with high ferroptotic gene expression being linked to lower survival. Overall, this study highlights the dual role of ferroptosis in cancer and suggests that ferroptosis inhibition, rather than induction, is a viable therapeutic strategy.

Kim R, Hashimoto A, Markosyan N, Tyurin VA, Tyurina YY, Kar G, et al. Ferroptosis of tumour neutrophils causes immune suppression in cancer. Nature 2022;612:338–46.

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