Microbial Determinants of Immune Activation and Clinical Outcome in Lung Tumor Subtypes

The tumor-associated microbiome is increasingly recognized as a critical modulator of cancer progression and therapy response, yet its composition and functional relevance in human lung tumors remain poorly defined. In this study, we profiled the bacterial and fungal communities of lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) and investigated how microbial patterns relate to tumor differentiation, immune contexture, and transcriptomic programs. LUAD and LUSC exhibited distinct microbial signatures, with LUAD showing lower microbial diversity and enrichment of genera associated with mucosal health. Within LUAD, differentiation status emerged as a key ecological and clinical variable: differentiated tumors were enriched in beneficial genera such as Akkermansia and Muribaculum , which correlated with CD8⁺ T cell infiltration and immune activation gene expression. In contrast, undifferentiated LUAD displayed increased abundance of pro-inflammatory or pathogenic taxa, including Lactococcus and Thermus , alongside reduced cytotoxic immune infiltration and elevated PD-L1 expression. Transcriptomic analysis revealed immune-related pathways in differentiated tumors and proliferative, MYC-driven programs in undifferentiated tumors. Integrated microbiota-transcriptome correlation and co-occurrence network analyses further delineated two distinct ecosystems: an immune-permissive, metabolically stable microbiota in differentiated LUAD versus a dysbiotic, immune-suppressive community in undifferentiated tumors. Functional predictions reinforced these trends, linking beneficial taxa to SCFA production and epithelial homeostasis, and harmful taxa to lipopolysaccharide biosynthesis and immune evasion. Collectively, these findings reveal that LUAD differentiation shapes the composition, structure, and function of the tumor microbiome, with implications for prognosis, immune responsiveness, and microbiota-informed therapeutic strategies.