Fusobacterium nucleatum confers resistance to PD-1 blockade therapy in colorectal cancer

Accumulating evidences suggest that gut microbiota modulates the therapeutic efficacy of immunotherapy.However, the link between gut microbiota and immunotherapy in colorectal cancer remains unknown. Here, we demonstrated that Fusobacterium nucleatum was enriched in patients who did not respond to PD-1 blockade by metagenomic sequencing. The high amount of F.nucleatum limited PD-1 mAb efficacy in tumor models. Mechanistically, F.nucleatum targeted EZH2-mediated histone H3 lysine 27 trimethylation to repress cGAS-interferon-b pathway, decreased tumor production of Th1-type chemokines CCL5 and CXCL10, limited CD8+ T cells trafficking to tumor microenvironment, consequently dampened anti-tumor response of PD-1 blockade. Treatment with metronidazole reduced F.nucleatum load, increased the intratumoral CD8+ T cells, improved the PD-1 mAb response in tumor-bearing mice. Clinically, a high abundance of F.nucleatum was associated with poor immunotherapy response. Thus, detecting and eliminating F.nucleatum will yield a meaningful perspective of clinical decision-making and meliorate the outcome of colorectal cancer patients.