**Abstract**

Colorectal cancer (CRC) is considered the third most common cancer type and the second cause of cancer-related death worldwide, representing a significant global public health issue. Approximately 20% of patients present with metastatic disease, while up to 50% of those with early stages will eventually develop metastasis. During the last two decades, sustained efforts have been made to discover the molecular landscape of CRC and identify novel therapeutic targets. These efforts changed the treatment paradigm for CRC and improved survival significantly in metastatic disease. Immunotherapy represents a novel and exciting treatment option with promising results in gastrointestinal malignancies. The application of immunotherapy in CRC showed impressive results in a subset of patients with high microsatellite instability/deficient mismatch repair (MSI-H/dMMR) phenotype. An in-depth analysis of these particular MSI-H/dMMR tumors revealed that they are characterized by a high mutational load resulting in an increased number of neoantigens and a highly infiltrated tumor microenvironment. The Food and Drug Association (FDA) has recently approved immune checkpoint inhibitors (ICIs) pembrolizumab and nivolumab +/− ipilimumab for first-line and non-first-line therapy of MSI-H/dMMR metastatic CRC, contributing to the continuum of care in these patients. This chapter aims to overview the immune landscape and immunotherapeutic strategies in CRC.

**Keywords:** colorectal cancer, immunotherapy, pembrolizumab, nivolumab, ipilimumab, MSI-H/dMMR
