Microbiota-mediated indole metabolites facilitate liver metastasis by modulating gammadeltaT17 cells (PRJCA047607)
The gut microbiota-derived signals critically shape hepatic immune microenvironments to influence cancer progression; however, the precise contribution of gut microbiota to liver metastasis and its mechanisms remain largely elusive. Here, we unveil a critical role of microbiota-derived indole metabolites in promoting melanoma liver metastasis in a mouse model. Mechanistically, the gut microbiota promotes the expansion and activation of hepatic ?d T cells and subsequent IL-17A production, which collectively fosters the establishment of an immunosuppressive microenvironment in the liver. A specific subset of IL-17A+ IL-17F+ ?d T cells was identified in association with liver metastasis and regulated by the gut microbiota. Furthermore, microbiota-derived indole derivatives or indole-producing commensals were found to regulate this ?dT17 cell subset, consequently promoting melanoma liver metastasis. The absence of IL-17A or ?d T cells abolishes the promoting effect of gut microbiota or indole metabolites on liver metastasis. Collectively, our findings reveal a crosstalk between the gut microbiota and hepatic immune microenvironment in melanoma liver metastasis development, and identify critical cellular and molecular mediators with potential as effective targets for intervention in hepatic metastasis.