The microbiota influences both initiation, progression and therapy response in colorectal cancer (CRC). The underlying molecular mechanisms involve complex microbiota-immune-tumor interactions, which are incompletely understood. Using unique mouse models of different CRC stages, germ-free mouse technology, established in-vitro assays, and precious clinical CRC isolates, we will study oncogenic microbes and their disease driving mechanisms. We will build further on recent discoveries that genotoxic E.coli strains drive CRC development though epithelial binding mechanisms, and that also fungi, including Candida albicans can exacerbate CRC. We will closely examine the host-microbiota interactions which regulate virulence factors of these oncogenic microbes, including binding mechanisms and genotoxin production. In addition, we will study bacteria which promote response to immune checkpoint inhibition therapy in-vivo. Together, we present a pioneering in-vivo research project to unravel complex host-microbe interactions in CRC development and therapy.