Immunocheckpoint Inhibitors in Microsatellite-Stable or Proficient Mismatch Repair Metastatic Colorectal Cancer: Are We Entering a New Era?

SIMPLE SUMMARY: The majority of metastatic colorectal cancer cases are mismatch-repair-proficient and microsatellite-stable, and unfortunately this condition is associated with an inherent resistance to Immune Checkpoint Inhibitors. However, several trials are investigating the right way to overcome resistance in these tumors, so as to expand the application scope of immunotherapy. Future perspectives include mainly a combination of immune checkpoint inhibitors with chemotherapy and bevacizumab or cetuximab; sequential treatment with Temozolomide in O6-methylguanine-DNA methyltransferase (MGMT)-methylated tumors; validation of Immunohistochemical biomarkers of response, such as tumor mutational burden or Immunoscore. ABSTRACT: Colorectal cancer (CRC) is the third most frequent cancer and the second leading cause of cancer-related deaths in Europe. About 5% of metastatic CRC (mCRC) are characterized by high microsatellite instability (MSI) due to a deficient DNA mismatch repair (dMMR), and this condition has been related to a high sensitivity to immunotherapy, in particular to the Immune Checkpoint Inhibitors (ICIs). In fact, in MSI-H or dMMR mCRC, treatment with ICIs induced remarkable response rates and prolonged survival. However, the majority of mCRC cases are mismatch-repair-proficient (pMMR) and microsatellite-stable (MSS), and unfortunately these conditions involve resistance to ICIs. This review aims to provide an overview of the strategies implemented to overcome ICI resistance and/or define subgroups of patients with MSS or dMMR mCRC who may benefit from immunotherapy.