Immunotherapy in Colorectal Cancer: Current and Future Strategies

Despite the recent advances in the systemic treatment of metastatic colorectal cancer (mCRC), prognostic outcomes have remained to be poor. Thus, what is needed is an innovative treatment approach. Immune checkpoint inhibitors (ICIs) targeting programmed death-1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) have exhibited a durable response and dominated the treatment of various tumor types. However, in mCRC, the clinical benefit is limited in patients with deficient mismatch repair (dMMR)/high levels of microsatellite instability (MSI-H), comprising approximately 5% of mCRC cases, and some do not respond to ICI treatment. Thus, further research is needed to identify predictive biomarkers. The most urgent need is developing effective immunotherapy for patients with proficient mismatch repair (pMMR)/microsatellite stable (MSS) cancer, which comprises 95% of mCRC cases. Tumors with the pMMR/MSS phenotype often exhibit a lower tumor mutation burden and fewer tumor-infiltrating lymphocytes than dMMR/MSI-H, leading to immune tolerance and evasion in the tumor microenvironment. Therefore, a number of investigative studies aimed at overcoming tumor resistance in current immunotherapy approaches are underway. A better understanding on the complexity and diversity of the immune system's functioning within the tumor microenvironment will increase the potential for developing predictive biomarkers and novel therapeutic strategies to potentiate anti-tumor immunity in patients with mCRC. In this review, we summarize the most recent advances in immunotherapy based on the findings of pivotal clinical trials for patients with mCRC, highlighting potent therapeutic approaches and predictive biomarkers.