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.

Metastatic colorectal cancer (mCRC) with mutated BRAF exhibits distinct biological and molecular features that set it apart from other subtypes of CRC. Current standard treatment for these tumors involves a combination of chemotherapy (CT) and VEGF inhibitors. Recently, targeted therapy against BRAF and immunotherapy (IT) for cases with microsatellite instability (MSI) have been integrated into clinical practice. While targeted therapy has shown promising results, resistance to treatment eventually develops in a significant portion of responsive patients. This article aims to review the available literature on mechanisms of resistance to BRAF inhibitors (BRAFis) and potential therapeutic strategies to overcome them.