Immunotherapy has been successfully applied clinically to treat a wide range of hematological and solid metastatic malignancies. The most widely used drugs targeting immune checkpoints, such as programmed cell death protein 1 (PD-1) and its ligand PD-L1, are effective in a subset of cancer patients. However, anti-PD-1/PD-L1 therapy has little effect on the majority of colorectal cancer patients. Thus, it is necessary to find a new approach that can improve the effectiveness of anti-PD-1/PD-L1 therapy.

Fusobacterium nucleatum (Fn) has previously been proven to be a cancer-promoting bacterium in colorectal cancer (CRC), which increases chemoresistance and suppresses the immune system. However, a study published in Signal Transduction and Targeted Therapy by Qin Huanlong's team at Shanghai Tenth People's Hospital of Tongji University titled "Fusobacterium nucleatum enhances the efficacy of PD-L1 blockade incolorectal cancer" found that Fusobacterium nucleatum enhances anti-PD-L1 immunotherapy in CRC treatment, and elucidated the related mechanism of action.

In this study, researchers analyzed a total of 41 CRC patients treated with PD-1 blockade and found that patients with higher levels of Fusobacterium nucleatum had longer progression-free survival (PFS) and better outcomes.

Researcher developed a mouse model to study the effect of Fusobacterium nucleatum. Wild-type CT26 mouse colon cancer cells were implanted subcutaneously into BALB/c mice, then Fusobacterium nucleatum, Escherichia coli, and phosphate buffer were injected into the tumor separately. Anti-PD-L1 monoclonal antibodies were injected intraperitoneally into the mice, along with isotype controls. The researchers discovered that the combination treatment reduced tumor volume and mass considerably.

What role does Fusobacterium nucleatum play in PD-1 blockade therapy? To begin, it is known that the activity and content of tumor-infiltrating lymphocytes are major factors in the efficacy of immune checkpoint therapy, and that such effector cells promote antitumor immune responses, so the researchers examined how the combination of Fusobacterium nucleatum and anti-PD-L1 therapy would affect tumor-infiltrating lymphocytes. Fusobacterium nucleatum enhanced the number of CD8+ tumor-infiltrating cells in mice, according to the findings. Furthermore, the researchers discovered an enhanced concentration of IFN-γ in CD8+ tumor-infiltrating cells, which has anticancer and immunomodulatory effects. As a result, Fusobacterium nucleatum combined treatment raised not only the number of CD8+ tumor-infiltrating cells, but also the amount of IFN-γ, thereby enhancing the anticancer effect of PD-1 blocking therapy.

Fusobacterium nucleatum also improved the therapeutic efficacy of PD-L1 inhibition by stimulating the STING signaling pathway, which in turn activated NF-κB signaling and upregulated PD-L1 expression. Fusobacterium nucleatum also boosted the concentration of PD-1+ cells in tumor-bearing mice treated with anti-PD-L1 monoclonal antibody, implying that it can enhance the anti-tumor effects of PD-L1 inhibition in a CRC mouse model via modulating PD-1 and PD-L1 expression.

Notably, the researchers also analyzed the clinical effects. The results showed that exposure to Fusobacterium nucleatum improved the response to PD-L1 blockade therapy in CRC patient-derived organoids.

Overall, this research shows that Fusobacterium nucleatum is conducive to CRC immunotherapy, dramatically improves the anticancer effect, and may be used as a biomarker for clinical prediction of PD-1/PD-L1 blockade success.