Adenocarcinomas of the small intestine are rare tumors but their incidence is increasing. There is a slight male predominance. The median age at diagnosis is the 6th decade. The most frequent primary location is the duodenum. There is no clearly identified environmental risk factor, but adenocarcinomas of the small intestine are associated in almost 20% of cases with predisposing diseases (Crohn’s disease, Lynch syndrome, familial adenomatous polyposis, Peutz–Jeghers syndrome and celiac disease).

Microsatellite instability (MSI) is a tumor phenotype related to a deficient DNA mismatch repair system (dMMR). This phenotype, observed in 5% of metastatic mCRC but 10–18% of localized CRC, is associated with high tumor mutational burden with highly immunogenic neoantigens. It has emerged as a major predictive biomarker for the efficacy of ICIs. In this review, we will present a comprehensive overview of the literature concerning the efficacy of ICIs in MSI/dMMR mCRC, with a focus on new developments in first-line metastatic setting. Then, we will present current and future challenges of immuno-oncology for patients with MSI/dMMR metastatic CRC.