Colorectal cancer (CRC) is the second leading cause of cancer death worldwide, accounting for approximately 880,000 deaths in 2018 [1]. Approximately 70–80% of patients with stage I–III CRC can be treated with curative surgical resection [2], and the 5-year survival rate for early-stage CRC is approximately 90%. However, the survival rate drops to only 10–15% for metastatic (stage IV) CRC [3]. Patients with stage IV CRC are mainly treated with fluorouracil-based chemotherapies, in combination with epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) inhibitors, and the median life expectancy is in the range of 21.3 to 30.1 months [4,5,6,7].

CRC is the most common gastrointestinal (GI) cancer. Compared with other tissues, the gastrointestinal tract is home to an enormous number of commensal bacteria and potential pathogens [8]. Therefore, the immune system in the colon and rectum has to fine-tune the balance of the maintenance of tolerance to self-tissue and immunity against potential pathogens and tumorigenic cells. Disruption of the GI tract’s normal immune homeostasis may cause autoimmunity diseases, including inflammatory bowel disease [9]. In contrast, normal immunosurveillance is critical to eliminate potential pathogens and eradicate sporadic tumorigenic cells to prevent GI diseases, including CRC.

It has been well recognized that the immune system plays a key role in colorectal cancer development and progression [10]. The presence of CD8⁺ T cells in the tumor bed and invasive margin is strongly associated with disease-free survival and overall survival in CRC and the “immune score”, quantifying the density and location of immune cells within the tumor, has provided prognostic value that may be superior to the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) tumor (T), nodes (N), and metastases (M) (TNM) classification in CRC [11,12]. This indicates that adaptive immune response may play a role in CRC progression [13] and immunotherapy may be promising in CRC treatment. However, the efficacy of immune checkpoint inhibitor monotherapy targeting programmed cell death-1 (PD-1) is only seen in a small subset of patients with microsatellite instability high (MSI-H) status. In contrast, no objective response was observed in microsatellite stable (MSS) CRCs, which account for the majority of the cases [14]. The mechanisms for resistance to anti-PD-1 immune checkpoint blockade in MSS CRC include lack of tumor neoantigens, immune exclusion, and immunosuppression. Higher tumor mutation burden (10- to 50-fold) and more neoantigens in MSI-H tumors, together with higher levels of multiple checkpoints, including PD-1, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and lymphocyte activation gene 3 (LAG3) in MSI-H tumors, may explain in part why anti-PD-1 treatment works more efficiently in MSI-H CRCs than in MSS CRCs [15,16]. With the recent advancement in combination strategies and immunomodulatory monoclonal antibodies (mAbs) targeting other immune checkpoints, there is great enthusiasm in developing novel immunotherapies in CRC.

In this review, we will focus on the systemic review of the mechanisms of immunosuppression and the clinical approaches to circumvent immunosuppression in CRC.