Lung cancer is a leading cause of cancer mortality, with non-small cell lung cancer (NSCLC) comprising the majority of cases. Despite the advent of immune checkpoint inhibitors (ICIs), a significant number of patients fail to achieve a durable response, highlighting the need to understand the factors influencing treatment efficacy. Saliva samples and tumor samples were collected from 20 NSCLC patients. The salivary microbiota was profiled using metagenomic next-generation sequencing, and metabolites were analyzed via liquid chromatography-mass spectrometry to identify correlations among bacteria, metabolites, and immunotherapy responses. Immunohistochemistry (IHC) analysis of tissue samples verified the result. Besides, in vitro experiments and tumor tissue microarray, including 70 NSCLC patients, were utilized to further explore the potential mechanism linking the oral microbiome and immunotherapy efficacy. The study revealed several differential species and distinct metabolite compositions between responders and non-responders to ICI therapy in NSCLC and explored correlations and mechanisms between microbiota metabolites and immunotherapy resistance. Notably, it was found that several Neisseria and Actinomyces species were significantly enriched in responders and 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 dysbiosis is correlated with immunotherapy resistance through regulation of CD8⁺ T cell activity/infiltration and PD-L1 expression. Specific saliva microbiome and its associated lipids metabolites are significantly associated with the efficacy of ICI-based therapy in lung cancer. Our findings suggest that oral microbiome modulation and targeting lipid metabolism could improve immunotherapy responses, offering new avenues for personalized treatment strategies.IMPORTANCEIn non-small cell lung cancer, our study links specific salivary microbiome profiles and related lipid metabolites to the efficacy of immune checkpoint inhibitor (ICI) therapies. Responders showed enrichment of certain Neisseria and Actinomyces species and distinct lipid compositions. These lipids correlate with PD-L1 expression and CD8⁺ T cell activity, affecting treatment outcomes. Our results imply that modulating the oral microbiome and targeting lipid metabolism may enhance ICI effectiveness, suggesting novel personalized therapeutic approaches.

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