Targeting MSS colorectal cancer with immunotherapy: are we turning the corner?

Introduction Immunotherapy with checkpoint inhibition has shown potent antitumor activity in patients with microsatellite instability (MSI) metastatic cancer. Microsatellite stable (MSS) colorectal cancer has long been considered resistant to immunotherapy.Areas covered In this review, we provide an overview of current progress on strategies to overcome the resistance to immunotherapy in MSS colorectal cancer.Expert opinion Emerging evidence suggest that combination of immune modulators such as regorafenib may improve the responsiveness of MSS colorectal cancer to checkpoint blockade. In addition, signs of clinical activity have also been observed in other combination strategies, such as the combination of checkpoint blockade with Stat3 inhibitor, or bispecific T-cell engagers. Nevertheless, predictive biomarkers that can identify patients who may benefit from immunotherapy are key for its implementation in clinical setting. Metastatic disease sites may predict for the response or resistance to checkpoint blockade, with liver metastases emerging as a strong predictive biomarker of lack of benefit from PD-1 targeting, even with combination therapies. Additional efforts are required to study the mechanism of resistance and to develop novel therapeutic strategies to overcome immune resistance.Abbreviations CEA: carcinoembryonic antigen; CR: complete response; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; DCR: disease control rate; MSI-H: microsatellite instability-high; MSS: Microsatellite stable (MSS); OS: overall survival; PD-1: programmed cell death protein 1; PD-L1: programmed death-ligand receptor 1; PR: partial response; PFS: progression-free survival; SD: stable disease; TMB: tumor mutation burden; VEGFR: vascular endothelial growth factor receptor