A fundamentally important biological question is how our bodies maintain a critical balance between inflammation and immune tolerance, and how this may be modified or evaded by cancers. The human colon, a tissue where many inflammatory diseases and cancers arise, performs this balancing act basally in the presence of dietary antigens and the normal microbiome. Within this homeostatic state, colorectal polyps and colorectal cancer (CRC) arise and can evade clearance by the immune system despite treatment by immune checkpoint inhibitors. We hypothesize that these pre-malignant lesions subvert the default tolerogenic state of the colon and induce additional immunosuppressive mechanisms. Deciphering the complex interaction between the epithelium, immune system and microbiome requires expertise of a talented group of researchers with complementary expertise. The unique composition of this ‘MIMICRY’ iBOF consortium aims to combine human samples, state-of-the-art immunology, novel tools, and in vivo mouse models to study the multi-factorial aspects of colorectal cancers. These will help develop novel immunotherapeutic strategies.