Fusobacterium nucleatum ‐Derived Outer Membrane Vesicles Promote Immunotherapy Resistance via Changes in Tryptophan Metabolism in Tumour‐Associated Macrophages

Only a minority of patients with head and neck squamous cell carcinoma (HNSCC) respond favourably to immunotherapy. The oral oncogenic bacterium Fusobacterium nucleatum (F.nucleatum) was recently observed to suppress the anti-tumour immune response, although the mechanisms remain unclear. In this study, we found that outer membrane vesicles (OMVs) derived from F.nucleatum (F.n-OMVs) promoted HNSCC progression by inducing immunosuppressive phenotypes of tumour-associated macrophages (TAMs), resulting in decreased cytotoxic T lymphocyte infiltration in vivo. Mechanistically, TAMs internalized tryptophanase presented in F.n-OMVs, which activated the tryptophan-2,3-dioxygenase 2/aryl hydrocarbon receptor (TDO2/AHR) pathway and upregulated the transcription of immunosuppressive cytokines and immune checkpoints. TDO2 inhibitor enhanced the therapeutic effect of anti-programmed death-1 in a tumour-bearing mouse model. Both TDO2 and F.nucleatum demonstrated excellent performance in predicting the immunotherapy outcomes in patients with HNSCC. These results indicate that F.n-OMVs induce immunotherapy resistance in HNSCC, providing novel insights into the microbiota-tumour immunity crosstalk.