Language

English

Publication Date

4-8-2025

Journal

Immunity

DOI

10.1016/j.immuni.2025.03.002

PMID

40157359

PMCID

PMC11981829

PubMedCentral® Posted Date

4-8-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

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.

Keywords

Triple Negative Breast Neoplasms, Humans, Neutrophils, Arachidonic Acid, Female, Drug Resistance, Neoplasm, Animals, Mice, Cell Line, Tumor, Tumor Microenvironment, Immune Checkpoint Inhibitors, Programmed Cell Death 1 Receptor

Published Open-Access

yes

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