F. nucleatum-derived succinic acid induces tumor resistance to immunotherapy in colorectal cancer

At present, the mechanisms underlying the association between gut microbiota metabolites and immunotherapy in CRC remain unknown. Here, we conducted a multiomics analysis of a cohort of patients with mCRC and found that F.nucleatum was more abundant in patients who did not respond to immunotherapy. We also found that F. nucleatum diminished the sensitivity to anti-PD-1 mAb through its metabolite succinic acid. Accordingly, patients with lower serum succinic acid levels achieved a better response to immunotherapy. Mechanistically, F.nucleatum-derived succinic acid suppressed the cGAS-interferon-ß pathway, consequently dampening the antitumor response by limiting CD8+ T-cell trafficking to the tumor microenvironment in vivo. Treatment with metronidazole reduced intestinal F.nucleatum abundance and thereby decreased serum succinic acid levels, thus resensitizing the tumors to immunotherapy in vivo. Collectively, our findings indicate that F. nucleatum and its metabolite succinic acid induce tumor resistance to immunotherapy and offer new insights into microbiota-metabolite-immune crosstalk in CRC. Overall design: We investigated the effect of Fusobacterium nucleatum on anti-PD-1 therapy in Germfree C57B/L6 MC38-tumor bearing mice. Tumor 11, 17, 18 and 19 were subcutaneous tumor from anti-PD-1 group;tumor 36, 37, 39,40 were subcutaneous tumor from anti-PD-1 + F. nucleatum group.