Colorectal cancer (CRC) is the third most common type of cancer and has a very high mortality rate. Increasing evidence shows that the microbiota influences both cancer initiation, progression and therapeutic response. The underlying mechanisms are incompletely understood, but involve cross-interaction between microbiota, immune and tumor components. Despite high success rates in other cancer types, immune checkpoint inhibition therapy (ICI), is not efficacious in most prevalent CRC subtypes. Observations in melanoma and lung cancer indicate that microbiota composition is a critical determinant of ICI efficacy. Therefore, we hypothesize that microbiota modulation during ICI therapy is essential to improve its efficacy in CRC. We propose to study the impact of microbiota in CRC immunity and immune therapy, using a unique in house-developed mouse model of CRC (Zeb2IEC-tg/+). In our new CRC model, tumor development critically depends on both the microbiota and the myeloid immune compartment. Therefore, this model represents a unique experimental platform to study the interplay between immunity- microbiota-tumor compartments. We will study the contribution of various immune components and evaluate immunological and microbiome interventions to assess CRC development and immune therapy efficacy. This study will open new perspectives for microbiota-immune based diagnostics and therapeutics in CRC.