Current Landscape and Potential Challenges of Immune Checkpoint Inhibitors in Microsatellite Stable Metastatic Colorectal Carcinoma

SIMPLE SUMMARY: The implementation of immunotherapy in the therapeutic landscape of colorectal carcinoma has been difficult due to the inefficacy reported in early clinical trials. Nevertheless, a small subset of tumors deficient in DNA mismatch repair proteins show excellent responses to immune checkpoint inhibitors, with long-lasting results. Most of our patients do not have these alterations and, therefore, immunotherapy appears not to be effective. In the current review, we attempt to describe the main mechanisms of resistance to immunotherapy presented by these tumors, how to cope with them, and the potential use of other biomarkers of response to immunotherapy. ABSTRACT: Colorectal cancer (CRC) is the third most frequent cancer and the second most common cause of cancer-related death in Europe. High microsatellite instability (MSI-H) due to a deficient DNA mismatch repair (dMMR) system can be found in 5% of metastatic CRC (mCRC) and has been established as a biomarker of response to immunotherapy in these tumors. Therefore, immune checkpoint inhibitors (ICIs) in mCRC with these characteristics were evaluated with results showing remarkable response rates and durations of response. The majority of mCRC cases have high levels of DNA mismatch repair proteins (pMMR) with consequent microsatellite stability or low instability (MSS or MSI-low), associated with an inherent resistance to ICIs. This review aims to provide a comprehensive analysis of the possible approaches to overcome the mechanisms of resistance and evaluates potential biomarkers to establish the role of ICIs in pMMR/MSS/MSI-L (MSS) mCRC.