Tumor-Suppressing Multi-Enterobacteria enhance the anti-PD-1/PD-L1 efficacy in microsatellite stable colorectal cancer

Gut microbiome significantly influences immunotherapy responses in colorectal cancer (CRC) treatment. While individual enterobacteria have been identified as enhancers of anti-PD-1/anti-PD-L1 therapy, the synergistic effects of multiple enterobacteria remain underexplored. To fill the gap, we introduced Tumor-Suppressing Multi-Enterobacteria (TSME), a consortium of nine beneficial intestinal probiotic strains, and investigated its impact on the anti-PD-1/anti-PD-L1 therapy for microsatellite stable (MSS) CRC. Using a tumor-bearing mouse model and genomic sequencing techniques, our research demonstrated that TSME significantly improved therapy efficacy by optimizing tumor immune microenvironment. Specifically, the addition of TSME notably increased CD8+ T infiltration, modulated cytokine profiles, and up-regulated crucial immune-related pathways, including TNF and JAK-STAT. Additionally, TSME altered intestinal microbial composition, enriching beneficial bacteria such as Akkermansia and Alistipes. These findings suggest that the well-engineered multi-enterobacteria could significantly enhance the effectiveness of immunotherapy for MSS CRC by synergistically modulating the immune and microbial landscapes.