Combination Immunotherapies to Overcome Intrinsic Resistance to Checkpoint Blockade in Microsatellite Stable Colorectal Cancer

SIMPLE SUMMARY: Immune checkpoint inhibitors have revolutionized the treatment landscape of microsatellite instable colorectal cancer. However, their efficacy is very limited in patients with microsatellite stable colorectal cancer. Recent preclinical and clinical studies have suggested the involvement of various tumor cell-intrinsic and tumor microenvironmental mechanisms in primary resistance to immunotherapy in microsatellite stable colorectal cancer. Because microsatellite stable colorectal cancers are immunologically heterogeneous with different immune evasive mechanisms, it is critical to precisely identify the major mechanism of resistance in each patient and to accordingly apply personalized combination immunotherapy strategies. ABSTRACT: Although immune checkpoint inhibitors (ICIs) have shown promising results in the treatment of treating various malignancies, progress has been severely limited in metastatic colorectal cancer (mCRC). ICIs are effective in a fraction of patients with microsatellite instability-high mCRC but have little clinical efficacy in patients with microsatellite stable (MSS) mCRC, which accounts for 95% of mCRC cases. MSS mCRCs are considered to have intrinsic resistance to ICI monotherapy through multiple mechanisms. (1) They are poorly immunogenic because of their low tumor mutation burden; (2) frequent activation of the WNT/β-catenin signaling pathway excludes intratumoral CD8(+) T cell immunity; (3) the tumor microenvironment is immunosuppressive because of the presence of various immunosuppressive cells, including tumor-associated macrophages and regulatory T cells; and (4) frequent liver metastasis in MSS mCRC may reduce the efficacy of ICIs. To overcome these resistance mechanisms, combination approaches using various agents, including STING agonists, MEK inhibitors, VEGF/R inhibitors, WNT/β-catenin inhibitors, oncolytic viruses, and chemo/radiotherapy, are actively ongoing. Preliminary evidence of the efficacy of some has been shown in early clinical trials. This review summarizes novel combination immunotherapy strategies described in recent preclinical and clinical studies to overcome the limitations of ICI monotherapy in MSS mCRC.