M.P. Roberti and C. Rauber aim to investigate the influence of gut microbiota-derived metabolites on CRC metastasis with a special focus on their modulation of tumour intrinsic pathways of immune recognition. Previously, M.P. Roberti and C. Rauber have demonstrated in preclinical models that response of microsatellite stable (MSS) CRC to immune checkpoint inhibitors (in combination with chemotherapy) depends on intestinal microbiota and is mediated by systemic effects on the immune system. Furthermore, M.P. Roberti and C. Rauber recently demonstrated that ketone body and bile acid metabolism also impacted therapy response in tumours. Based on these findings, they hypothesise that gut microbiota-derived metabolites in the blood can impact distant metastasis by altering tumour intrinsic gene expression pathways that determine tumour immunogenicity, thus altering tumour immunosurveillance and response to treatment. To test this hypothesis, they will characterise gut-microbiota metabolites in CRC samples, and then apply their high throughput immunoprofiling platform in CRC cell lines and PDOs to identify and validate microbiota-derived metabolites that modulate tumour intrinsic pathways of immune recognition. Finally, potential candidates will be tested in murine orthotopic CRC metastasis models to identify metabolites that can sensitise MSS-CRC tumours to immunotherapies.