Abstract Background Lung cancer remains the leading cause of cancer-related mortality globally, with limited efficacy of current therapies due to drug resistance and poor early diagnosis. Tumor-resident microbiota and their derived exosomes play critical roles in tumor microenvironment remodeling and progression, yet the underlying mechanisms remain unclear. Methods We collected tumor tissues from early and advanced-stage lung cancer patients, isolated exosomes via ultracentrifugation, and performed 16S rRNA gene sequencing (V2/V3/V5/V6/V8 regions) to profile exosome-derived microbiota. Bioinformatics analyses were conducted using TCGA, HPA, and ExMdb databases to identify key genes (NDRG1, P4HB, VDAC1, CDK1) associated with exosomes, siderophores, and lung cancer staging. In vitro experiments used A549 cells co-cultured with Burkholderia cepacia, and in vivo studies employed nude mouse xenograft models. Phenotypic assays and molecular experiments (qPCR, Western blot, immunofluorescence) validated gene expression and pathway activation. Results Advanced-stage lung cancer tissues exhibited significantly higher exosome secretion from microbiota than early-stage tissues. Alpha diversity (Observed species, Shannon index) showed no difference in microbial richness/diversity between stages, while Beta diversity (Unweighted UniFrac) revealed distinct microbial community composition (*p*0.05).The Burkholderia cepacia was enriched in advanced-stage tissues and correlated with enhanced tumor growth in xenografts (tumor volume: *p*0.001). Functional prediction indicated enrichment in “siderophore biosynthesis” pathway. NDRG1, P4HB, VDAC1, and CDK1 were highly expressed in lung cancer tissues, correlated with tumor staging, and predicted poor prognosis. Conclusions The Burkholderia cepacia enriches in advanced lung cancer and promotes progression via exosomes, which regulate NDRG1/P4HB/VDAC1/CDK1 axis and downstream pathways. This study provides a novel microbiota-exosome-host gene interaction model for lung cancer diagnosis and targeted therapy. This abstract is funded by: National Natural Science Foundation of China
Han et al. (Fri,) studied this question.