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

Immune checkpoint blockade therapy with anti-PD-1 monoclonal antibody (mAb) is a treatment for colorectal cancer (CRC). However, some patients remain unresponsive to PD-1 blockade. The gut microbiota has been linked to immunotherapy resistance through unclear mechanisms. We found that patients with metastatic CRC who fail to respond to immunotherapy had a greater abundance of Fusobacterium nucleatum and increased succinic acid. Fecal microbiota transfer from responders with low F. nucleatum, but not F. nucleatum-high non-responders, conferred sensitivity to anti-PD-1 mAb in mice. Mechanistically, F. nucleatum-derived succinic acid suppressed the cGAS-interferon-β pathway, consequently dampening the antitumor response by limiting CD8+ T cell trafficking to the tumor microenvironment (TME) in vivo. Treatment with the antibiotic metronidazole reduced intestinal F. nucleatum abundance, thereby decreasing serum succinic acid levels and resensitizing tumors to immunotherapy in vivo. These findings indicate that F. nucleatum and succinic acid induce tumor resistance to immunotherapy, offering insights into microbiota-metabolite-immune crosstalk in CRC. [Display omitted] •High abundance of F. nucleatum correlates with decreased efficacy of immunotherapy in CRC•F. nucleatum diminished the sensitivity to anti-PD-1 mAb through succinic acid•Succinic acid decreased anti-PD-1 mAb sensitivity by impairing CD8+ T cell immunity•Elimination of intestinal F. nucleatum resensitizes tumors to immunotherapy in CRC Jiang et al. report that F. nucleatum-derived succinic acid diminished sensitivity to anti-PD-1 mAb in colorectal cancer by impairing CD8+ T cell-mediated antitumor immunity. These findings offer insights into microbiota-metabolite-immune crosstalk in colorectal cancer and potential strategies for improving clinical response to immunotherapy.