Ferroptotic neutrophils eradicate chemotherapy-induced immunity in breast cancer (Neutrophils)

Inducing ferroptosis in tumor cells serves as a promising strategy for treating malignancies that are refractory to traditional treatment modalities. However, the consequences of ferroptosis in immune cells in the tumor microenvironment (TME) are not completely understood. In this study, we found that neutrophils in chemoresistant breast cancer exhibited notable vulnerability to ferroptosis. In chemoresistant neutrophils, the cellular phospholipid profile was reprogrammed owing to a deficiency in membrane-bound O-acyltransferase domain-containing 1 (MBOAT1), shifting the preference of the phospholipid fatty acid pattern from monounsaturated fatty acids (MUFAs) to polyunsaturated fatty acids (PUFAs), thereby increasing susceptibility to ferroptosis. Ferroptotic neutrophils significantly suppress the proliferation and cytotoxicity of antitumor CD8 T cells via PGE2, IDO, and oxidized lipids. Furthermore, we found that neutrophil ferroptosis was closely associated with a distinctive subset of IL-1+ CXCL3+ CD4 (Fer-CD4) T lymphocytes that were enriched in chemoresistant tumors. Fer-CD4 T cells regulated neutrophil ferroptosis through MBOAT1 modulation via IL-1/IL-1R1/NF-B signaling. Moreover, we revealed that there is crosstalk between neutrophils and Fer-CD4 T cells, during which Fer-CD4 T cells replenish the neutrophil pool of the TME via CXCL3, IL-8, and S100A9. The ferroptotic neutrophils in turn promote Fer-CD4 T cell differentiation, resulting in extensive neutrophil ferroptosis. In spontaneously tumorigenic mice, targeting IL-1+ CD4 T cells or IL-1R1+ neutrophils disrupted this crosstalk, suppressed neutrophil ferroptosis, enhanced antitumor immunity, and overcame chemoresistance. Our findings revealed the immune-reshaping capacity of neutrophil ferroptosis and its reciprocal feedback regulation with Fer-CD4 T cells, identifying promising targets for restoring anticancer immunosurveillance and reversing chemoresistance