Monocyte Preprogramming by Tobacco Carcinogens and Fructose Intake Accelerates Lung Cancer Progression via Metabolic and Epigenetic Pathways.

Although tobacco smoking is the leading cause of lung cancer (LC), excessive sugar intake has also emerged as a potential risk factor, yet its mechanistic contribution remains poorly defined. In this study, we investigated how high-fructose intake modulates the tobacco carcinogen-induced LC progression. Co-exposure to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and benzo[a]pyrene (NNK and BaP; collectively referred to as NB) combined with a high-fructose diet markedly accelerated tumor progression in multiple mouse models, including Kras-driven LC and LKB1-deficient (LKB1) lung tumors. NB-induced LC progression was suppressed by restricting glucose metabolism, indicating a metabolic dependency. Mechanistically, NB exposure stimulated transcriptional programs that promote monocyte/macrophage recruitment within the tumor microenvironment and enhanced fructose uptake through both transcriptional and post-transcriptional upregulation of fructose transporters, including glucose transporter 8 (GLUT8). This metabolic reprogramming increased acetylation of histones and signal transducer and activator of transcription 3 (STAT3), leading to transcriptional upregulation of genes governing macrophage differentiation and M2 polarization. Analysis of human LC samples revealed enrichment of pro-metastatic IL-10 and VEGFA M2 macrophages, which correlated with poor clinical outcomes. Collectively, these findings demonstrate that NB-driven fructose metabolism induces epigenetic reprogramming of macrophages to promote LC progression and identify pro-metastatic M2 macrophages as potential prognostic biomarkers and therapeutic targets.