What question did this study set out to answer?

This study aims to explore the combined effects of tobacco carcinogens and high-fructose intake on the progression of lung cancer.

April 7, 2026Open Access

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

JAJee Hwan AhnSeoul National University of Science and Technology HMHye-Young MinSeoul National University JKJisung KimSeoul National University

Key Points

This study aims to explore the combined effects of tobacco carcinogens and high-fructose intake on the progression of lung cancer.
Used multiple mouse models with Kras G12D and LKB1 deficiency to study tumor progression.
Monitored the effects of high-fructose diets alongside tobacco carcinogen exposure.
Analyzed human lung cancer samples for macrophage populations and clinical outcomes.
Co-exposure to tobacco carcinogens and high-fructose diet accelerated tumor growth.
Restriction of glucose metabolism inhibited tumor progression.
Identification of pro-metastatic M2 macrophages correlated with poor clinical outcomes in human samples.

Abstract

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 benzoapyrene (NNK and BaP; collectively referred to as NB) combined with a high-fructose diet markedly accelerated tumor progression in multiple mouse models, including Kras G12D/+ -driven LC and LKB1-deficient (LKB1 KO ) 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.

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