Microbiota-derived urocanic acid triggered by tyrosine kinase inhibitors potentiates cancer immunotherapy efficacy

Interactions between the host and the gut microbiota influence cancer progression and treatment responses. While the combination of tyrosine kinase inhibitors (TKIs) and immune checkpoint blockade (ICB) has improved outcomes, some cancer patients still have poor responses. The underlying mediators of this heterogeneity remain unclear. Here, we demonstrate that TKIs potentiate the immunotherapy response by increasing the abundance of Muribaculum and its metabolite, urocanic acid (UCA), which reduces myeloid-derived suppressor cell (MDSC) recruitment via the CXCL1-CXCR2 axis by inhibiting p65 in tumor vascular endothelial cells. Mechanistically, UCA selectively binds to the aspartic acid 31 residue of IκBα and suppresses its phosphorylation at serine 32. Compared with non-responders, clinical ICB responders present a higher UCA concentration and a greater level of Muribaculum gordoncarteri in feces, indicating both as potential predictive biomarkers for treatment response. Collectively, our findings reveal and highlight the important role of the gut microbial metabolite UCA in response to ICB.