Tumor-Derived Exosomal Fatty Acids Reprogram Neutrophils to Drive Neutrophil Extracellular Traps Formation and Lung Cancer Progression

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Tumor-infiltrating neutrophils are increasingly recognized as key drivers of cancer progression, but the mechanisms that govern their protumoral reprogramming remain elusive. Here, we demonstrated that lung cancer-derived exosomes (LDEs) deliver free fatty acids into neutrophils, triggering lipid accumulation, fatty acid β-oxidation, and mitochondrial reactive oxygen species production. This metabolic reprogramming culminates in enhanced neutrophil extracellular traps (NETs) formation, which accelerates lung cancer growth. Mechanistically, Ras-related protein Rab-34 (Rab34), a small guanosine triphosphatase, regulates neutrophil uptake of LDEs. Knockdown of Rab34 in neutrophils dramatically attenuated LDEs-induced lipid accumulation, fatty acid β-oxidation activation, and NETs formation, thereby mitigating neutrophil-involved lung cancer progression in vivo. Deoxyribonuclease I-mediated NETs degradation further confirmed the dependency of lung cancer growth on NETs. These findings uncovered a Rab34-dependent way by which LDEs reprogram neutrophils via exosomal free fatty acids, offering Rab34 and NET-associated pathways as potential therapeutic targets in lung cancer.

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