Exosomal MiR-4466 from Nicotine-activated Neutrophils Promotes Tumor Cell Stemness and Metabolism in Lung Cancer Metastasis

Smoking is associated with lung cancer and has a profound impact on tumor immunity. Nicotine, the addictive and non-carcinogenic smoke component, influences various brain cells and the immune system. However, how long-term use of nicotine affects brain metastases is poorly understood. We, therefore, examined the mechanism by which nicotine promotes lung cancer brain metastasis. In this study, we conducted a retrospective analysis of 810 lung cancer patients with smoking history and assessed brain metastasis. We found that current smoker's lung cancer patients have significantly higher brain metastatic incidence compared to the never smokers. We also found that chronic nicotine exposure recruited STAT3-activated N2-neutrophils within the brain pre-metastatic niche and secreted exosomal miR-4466 which promoted stemness and metabolic switching via SKI/SOX2/CPT1A axis in the tumor cells in the brain thereby enabling metastasis. Importantly, exosomal miR-4466 levels were found to be elevated in serum/urine of cancer-free subjects with a smoking history and promote tumor growth in vivo, suggesting that exosomal miR-4466 may serve as a promising prognostic biomarker for predicting increased risk of metastatic disease among smoker(s). Our findings suggest a novel pro-metastatic role of nicotine-induced N2-neutrophils in the progression of brain metastasis. We also demonstrated that inhibiting nicotine-induced STAT3-mediated neutrophil polarization effectively abrogated brain metastasis in vivo. Our results revealed a novel mechanistic insight on how chronic nicotine exposure contributes to worse clinical outcome of metastatic lung cancer and implicated the risk of using nicotine gateway for smoking cessation in cancer patients.