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 discovered that TNBC cells surviving anti-PD-1 and chemotherapy treatment accumulated neutral lipids. Disrupting lipid droplet formation in cancer cells reversed resistance and mitigated the immunosuppressive microenvironment. Single-cell RNA sequencing revealed 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) mediated neutrophil reprogramming. Blocking dietary intake of omega-6 fatty acids or inhibiting fatty acid elongation for AA synthesis restored antitumor immunity and re-sensitized the resistant tumors to anti-PD-1 and chemotherapy treatment. In human patients, AA metabolism-related pathways correlated with neutrophil enrichment. Overall, we demonstrate how lipid accumulation in TNBC cells leads to immune suppression and therapy resistance. Eighteen days after tumor implantation, three tumors from 2208L, 2208L-Res1 and 2208L-Res2 group were collected, and CD45+ immune cells were sorted out for single cell sequencing.