Abstract 5021: Multi-omics integration reveals interplay among intratumoral microbiome, host metabolism, and immune response in non-small cell lung cancer

Abstract The lung, constantly exposed to diverse microorganisms, harbors a microbiome that can influence disease development, including cancer, through mechanisms such as altered immune function and host metabolism. While intratumoral microbiota have been linked to cancer progression and therapy response, their specific role in lung cancer remains poorly understood. Microbial metabolites play a crucial role in mediating the host signaling and metabolic pathways. However, the precise connection between intratumoral microbiota and cancer metabolism is still unresolved. To address this, we comprehensively analyzed the relationship between intratumoral microbiota and host metabolism in 1, 111 NSCLC patients using data from TCGA and single-cell RNA sequencing samples. We identified 17 microbial genera associated with host metabolism through gene set variation analysis (GSVA) and Spearman correlation, further validated these associations through survival and differential abundance analyses. To uncover key pathways associated with specific microbes, we applied gene set enrichment analysis (GSEA) and weighted correlation network analysis (WGCNA). Drug sensitivity was assessed based on microbial profiles, while Scissor method identified microbe-associated immune cell subpopulations and their functional roles within the tumor microenvironment. Our findings revealed that Succinimonas and Marichromatium act as risk factors, while Luteibacter serves as a protector in NSCLC patients. High abundance of Succinimonas was associated with upregulated glycolysis, downregulated immune responses, enhanced imuune evasion and poorer survival outcomes. Additionally, Succinimonas abundance was associated with mutations in key tumor progression genes, such as TP53, SPTA1, and SYNE1. Single-cell analysis demonstrated that Succinimonas influenced T cell subpopulations, notably by downregulating Treg Helios- cells, potentially inhibiting antitumor immunity. Furthermore, Succinimonas abundance was associated with sensitivity to specific cancer drugs. This study uncovers the complex relationship among intratumoral microbiota, host metabolism, and immune responses in lung cancer. Succinimonas emerges as a critical microbial player influencing cancer metabolism, immune evasion, and treatment responses. Our findings provide a preliminary understanding of these interactions, further in vivo and in vitro studies exploring the impact of intratumoral microbes on cancer could potentially lead to novel therapeutic strategies for cancer treatment. Citation Format: Jihye Yang, Hyumin Woo, Siyoung Yang, Seong-il Eyun. Multi-omics integration reveals interplay among intratumoral microbiome, host metabolism, and immune response in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5021.