Immune checkpoint inhibitors (ICIs) have limited efficacy in microsatellite stable (MSS) metastatic colorectal cancer (mCRC), and combination therapy needs to be further explored. In this single-arm, open-label, phase II trial (NCT04745130), we evaluate the efficacy and safety of the combination therapy of antiangiogenesis (regorafenib) and ICI (sintilimab) in patients with MSS mCRC. The primary endpoint is overall survival (OS). Secondary endpoints include progression free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety. The median OS and PFS are 14.1 months (95% CI: 10.5-17.7) and 4.1 months (95% CI: 3.4-4.8), respectively. The ORR is 21.4%, DCR is 63.1%, and DoR is 13.0 months (95% CI: 2.5-23.5). Patients with RAS/RAF wild-type exhibit significantly longer median OS (23.3 months, 95% CI: 10.0-36.6) compared to those with mutations (12.1 months, 95% CI: 8.4-15.8). The combination therapy is well tolerated and has limited toxicity. Biomarker analysis, including transcriptome sequencing and multiplex immunohistochemistry staining are performed. The efficacy of this combination treatment is tied to specific gene expressions governing tumor metabolism. Moreover, the effectiveness of immunotherapy depends on the abundance of immune cells, as well as the distance between immune cells and tumor cells.