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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. In this review, we provide an overview of current progress on strategies to overcome the resistance to immunotherapy in MSS colorectal cancer. Emerging evidence suggest that combination of immune modulators such as regorafenib may improve the responsiveness of MSS colorectal can