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

ABSTRACT 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.