Retrospective Evaluation of the Inflammatory Network Linking the Microbiome to the Tumor Immune Microenvironment in Lung Squamous Cell Carcinoma

The intratumoral microbiota is emerging as a key modulator of tumor progression and responses to therapies. In this study, we investigated the role of the genus Lachnoclostridium in lung squamous cell carcinoma by analyzing paired microbiome and transcriptome data from 482 patients. We found that a high relative abundance of Lachnoclostridium was significantly associated with an inflamed tumor microenvironment, characterized by elevated immune infiltration, stromal content and expression of immune checkpoint genes, as well as a lower tumor immune dysfunction and exclusion score, suggesting a potentially enhanced response to immunotherapy. Leveraging this association, we developed a machine learning model based on Lachnoclostridium -related gene signatures, which demonstrated robust pan-cancer predictive performance for immune checkpoint inhibitor efficacy. Mechanistically, the Lachnoclostridium -high phenotype was linked to a potent local inflammatory response, marked by chemokine upregulation, which was further correlated with the activation of the epithelial-mesenchymal transition program, implying a role in prometastatic signaling. Furthermore, profiling of the intratumoral microbiota revealed distinct diversity, composition and network interactions across Lachnoclostridium abundance groups. Crucially, the abundance of Lachnoclostridium significantly influenced tumor cell sensitivity to various anti-cancer drugs, including BI-2536 and lapatinib. Collectively, our findings identify intratumoral Lachnoclostridium as a key modulator associated with the tumor immune microenvironment, inflammatory signaling and therapeutic response in lung squamous cell carcinoma. These associations have potential implications for predicting the outcomes of immune checkpoint inhibitor therapy and understanding the mechanisms of drug resistance.