Intratumorally specific microbial-derived lipopolysaccharide contributes to non-small cell lung cancer progression

As an emerging component of the tumor microenvironment (TME), the intratumoural microbiota imperceptibly influences the progression of various human malignancies. However, the critical intratumoural microbiota and its role in non-small cell lung cancer (NSCLC) progression have not been fully elucidated. Here, we used high-throughput sequencing and clinical samples analysis to identify the relationship between intratumoural bacteria and NSCLC progression. The results showed that significant abnormalities in the intratumoural microbiota of NSCLC. Specifically, the relative abundance of gram-negative bacteria in tumor was significantly increased, and network analysis revealed that <i>Escherichia-Shigella</i> and <i>unclassified_f__Enterobacteriaceae</i>, which have strong abilities to synthesize the bacterial toxin LPS, significantly promoted tumor proliferation. Mechanistically, we found that <i>Escherichia-Shigella-</i> and <i>unclassified_f__Enterobacteriaceae</i>-derived LPS activated the TLR4-mTOR-NF-κB-IL-6 axis to facilitate NSCLC cell proliferation, whereas rapamycin effectively delayed LPS-induced tumor cell proliferation in vitro and in vivo functional experiments. Receiver operating characteristic curves revealed that the combination of intratumoural bacterial concentration, <i>Escherichia-Shigella</i> abundance, <i>unclassified_f__Enterobacteriaceae</i> abundance, and LPS content had greater diagnostic validity in predicting the probability of NSCLC, and the detection of these factors in blood has potential for using the non-invasive diagnosis of NSCLC. Overall, this study revealed the mechanism by which LPS from specific bacteria in TME promoted tumor development, providing new strategies for NSCLC treatment and diagnosis from a microbial perspective.