salivary microbiome and metabolites

<b>Background:</b> Lung cancer is a leading cause of cancer mortality, with NSCLC comprising the majority of cases. Despite the advent of immune checkpoint inhibitors(ICIs), a significant number of patients fail to achieve durable respond, highlighting the need to understand the factors influencing treatment efficacy.<b>Methods:</b><b> </b>Salivasamples and tumor samplesfrom 20 NSCLC patientswere collected. The salivary microbiota was profiled using mNGS and the metabolites were analyzed via LC/MS to identify the correlationsamong bacteria, metabolitesand immunotheropy responses.Immunohistochemistry of tissue samplesverified the result. Besides, in vitro experimentsand tumor tissue microarryincluding 70 NSCLC patients further explore potential mechanism between the oral microbiome and immunotherapy efficacy.<b>Results:</b><b> </b>The study revealed several differential species and distinct metabolites compositions between responders and non-responders to ICIs therapyin NSCLC and explored correlations and mechanisms between microbiota metabolites and immunotherapy resistance. Notably, it was found that several Neisseria and Actinomyces species were significant enriched in respondersand identified lipids and lipid-like molecules associated with PD-L1 expression levels and treatment outcomes. Importantly, several differential lipid molecules were associated with differential species. Further, in vitro experiments and IHC experiments indicated that abnormal fat metabolism linked to dysbiosisare correlated with immunotherapy resistance through regulation of CD8+T cell activity/infiltration and PD-L1 expression .<b>Conclusion:</b><b> </b>Specific saliva microbiome and its associated lipids metabolites are significantly associated with the efficacy of ICIs-based therapy in lung cancer. The study's findings suggest oral microbiome modulation and targeting lipid metabolism could improve immunotherapy responses, offering new avenues for personalized treatment strategies.