Intratumoral Corynebacterium is associated with phospholipid metabolic reprogramming and spread through air spaces in...

Spread through air spaces (STAS) is an adverse invasive pattern in lung adenocarcinoma (LUAD), but reliable biomarkers for preoperative or intraoperative prediction remain limited. We investigated whether the intratumoral microbiome and metabolome are associated with STAS.

Fresh tumor and paired adjacent non-tumor lung tissues from resected LUAD were analyzed using 5-region 16S rRNA gene sequencing and untargeted metabolomics. Microbiome-metabolome correlations were assessed by Spearman analysis, and receiver operating characteristic curves were used to evaluate diagnostic performance. The clinical relevance of ABCA3 was further explored using GEPIA2. ABCA3 and MMP9 expression was additionally assessed in selected same-cohort tumor samples by qRT-PCR.

Tumor tissues displayed a distinct microbial composition characterized by Corynebacterium enrichment and a metabolomic profile marked by phospholipid remodeling. Corynebacterium abundance was positively correlated with phosphatidylcholine and sphingomyelin species, but negatively correlated with several amino acids. STAS-positive tumors showed higher Corynebacterium abundance and increased membrane-lipid accumulation than STAS-negative tumors. An integrated model combining Corynebacterium, PC(39:6), and SM(d18:1/17:0) showed high apparent discrimination in this exploratory cohort(AUC = 0.98), although external validation is required. In external transcriptomic analyses, higher ABCA3 expression was associated with better overall survival and was inversely correlated with MMP9 expression in LUAD. In selected same-cohort tumor samples, qRT-PCR showed significantly lower ABCA3 expression and higher MMP9 expression in the STAS-positive/Corynebacterium-enriched group than in the STAS-negative/Corynebacterium-low group.

Intratumoral Corynebacterium is associated with phospholipid metabolic reprogramming and a STAS-positive phenotype in LUAD. A combined microbial-metabolic signature may aid STAS risk stratification and suggests a potential association with ABCA3-related lipid homeostasis, but causal relationships require functional validation. Same-cohort qRT-PCR further supported an ABCA3-low/MMP9-high invasive expression pattern in the selected STAS-positive/Corynebacterium-enriched samples.