CNSC-99. Gut Microbiome Influences Survival, Tumor Immunity, and Dna Repair Activity in Glioblastoma: A Multi-Omics Human Study

INTRODUCTION The gut microbiome has been recognized as a modulator of immune responses and therapeutic outcomes in cancer. However, its role in glioblastoma remains underexplored. We investigated whether gut microbiome composition is associated with survival in glioblastoma and examined mechanistic links involving tumor immune infiltration and DNA repair. METHODS We analyzed stool, tumor, and plasma samples from 46 IDH-wildtype glioblastoma patients. Gut microbiome was analyzed via 16S rRNA sequencing, meanwhile, metabolites were evaluated by a targeted panel. Associations between taxa and survival were assessed using Cox proportional hazards modeling and linear discriminant analysis effect size. The Bacteroidaceae/Lachnospiraceae ratio was used to stratify microbiome-defined subgroups. Tumor transcriptomic data were generated using a 714-mRNA targeted panel. CD68, CD3, and CD8 were evaluated to quantify immune cell infiltration (n=20), and systemic immune status was assessed using 30-plex plasma cytokine profiling (n=34). RESULTS Higher Bacteroidaceae/Lachnospiraceae ratio was associated with longer survival (21.2-months vs. 13.7-months, HR=0.44, p=0.017). This was independent of age, MGMT promoter methylation, and extent-of-resection. Higher Lachnospiraceae abundance was associated with reduced CD68⁺ macrophage in tumor (p<0.05) and trends toward reduced CD3⁺ and CD8⁺ T-cell infiltration. These changes were not reflected in circulating cytokine levels or the abundance of major microbial metabolites, suggesting that Lachnospiraceae modulates immune exclusion through local mechanisms. Transcriptomic analyses revealed that tumors from high Lachnospiraceae patients exhibited downregulation of chemokine signaling, antigen presentation, and innate immune genes. In contrast, patients with low Bacteroidaceae abundance exhibited transcriptional upregulation of DNA repair pathways. Genes involved in homologous recombination and non-homologous end joining were significantly elevated. CONCLUSIONS Gut microbiome composition—particularly the balance between Bacteroidaceae and Lachnospiraceae—is strongly associated with survival in GBM. High Lachnospiraceae abundance contributes to a locally immunosuppressive tumor microenvironment, while low Bacteroidaceae abundance appears to promote enhanced DNA repair activity and therapy resistance.