Colorectal cancer (CRC), known as a frequently fatal disease, ranking as the third most common malignancy, is the second leading cause of cancer related mortality worldwide. Metastases are common in CRC patients which account for approximately 25% of the patients at diagnosis, 50% of patients during treatment which is associated closely with CRC mortality. Conventional therapies such as surgery, chemotherapy, and radiotherapy are standards of care for the treatment of CRC patients. However, primary tumor recurrence and secondary disease in patients receiving standard of care treatment modalities occur in 50% of patients so that new treatment modalities are needed. Immune checkpoint inhibition (ICI) has transformed the management of patients suffered from metastatic CRC (mCRC) with mismatch repair deficiency (dMMR) and microsatellite instability (MSI) -high (MSI-H) while manifests ineffectiveness in preserved mismatch repair (pMMR) or microsatellite stable (MSS) “cold” tumors which makes up the majority (95%) of mCRC. In this review, we mainly lay emphasis on the development of combinations in therapy strategies with ICIs with other immune based treatment approaches to increase the intra-tumoral immune response and render tumors ‘immune-reactive', thereby increasing the efficacy of tumor immunotherapy.