Tumor-derived arachidonic acid reprograms neutrophils to promote immune suppression and therapy resistance in triple-negative breast cancer.

The combination of immune checkpoint blockade and chemotherapies is the standard of care for triple-negative breast cancer (TNBC). However, initially, responsive tumors can still develop recurrences, suggesting acquired resistance mechanisms that remain poorly understood. Herein, we discover that TNBC cells surviving anti-programmed cell death protein-1 (anti-PD-1) and chemotherapy treatment accumulate neutral lipids. Disrupting lipid droplet formation in cancer cells reverses resistance and mitigates the immunosuppressive microenvironment. Single-cell RNA sequencing reveals a subset of neutrophils exhibiting a lipid-laden phenotype similar to adjacent tumor cells. Mechanistically, tumor-derived extracellular vesicles carrying lipids, including arachidonic acid (AA), mediate neutrophil reprogramming. Blocking dietary intake of omega-6 fatty acids or inhibiting fatty acid elongation for AA synthesis restores anti-tumor immunity and re-sensitizes the resistant tumors to anti-PD-1 and chemotherapy treatment. In human patients, AA metabolism-related pathways correlates with neutrophil enrichment. Overall, we demonstrate how lipid accumulation in TNBC cells leads to immune suppression and therapy resistance.