The LAMp-LC Study: Unveiling the lung microbiome in Australians with early- and late-stage lung cancer using shotgun metagenomics

Lung cancer remains the leading cause of cancer‑related mortality, yet the role of lower airway microbiota in disease development and progression is incompletely defined. Here, we characterised the lung microbiome in an Australian cohort (lung cancer n =106, healthy n =10) using shotgun metagenomics and semi‑quantitative culture to evaluate site-specific microbial ecology across the tumour microenvironment (TME), contralateral airways, and oral cavity, to evaluate microbiome differences across early‑ and late‑stage disease, and to quantify clinical covariate impacts on airway microbiota. Diversity analyses, multivariable linear modelling, and culture‑based comparisons were performed, with adjustment for smoking pack‑years, sex, and tumour characteristics. Cumulative smoking exposure caused significant, progressive core commensal depletion ( Neisseria subflava , Gemella sanguinis , Rothia mucilaginosa ), alongside Streptococcus mitis enrichment, with Mogibacterium diversum uniquely depleted within the TME of smokers. β diversity in both early- and late-stage bronchial washes (BWs) significantly diverged from healthy controls, whilst Shannon diversity (α diversity) was significantly reduced in early-stage compared with late-stage BWs. The early‑stage TME also demonstrated significantly reduced microbial cultivability compared with healthy and other lung cancer BWs. A small number of taxa were uniquely enriched ( Sporothrix and Pseudomonas species) or depleted ( Streptococcus parasanguinis , Streptococcus cristatus , R. mucilaginosa ) within the TME, and 13 taxa were significantly enriched or depleted in both TME and contralateral airways compared with healthy airways. Only lung adenocarcinoma showed distinct oral β‑diversity restructuring. Taken together, our findings demonstrate that the lung cancer microbiome is characterised by early and progressive lower airway dysbiosis that is strongly shaped by tumour presence. Our findings point to potential new avenues for microbiome‑based diagnostic and therapeutic strategies.