Identification of effective therapies for colorectal cancer (CRC) remains an urgent medical need, especially for the microsatellite-stable (MSS) phenotype. In the current study, a combination of fruquintinib plus anti-PD-1 for MSS CRC therapy was investigated. First, a case of advanced MSS CRC was reported. After failure of multiline therapy, the patient finally achieved rapid response after receiving fruquintinib plus anti-PD-1 treatment. Then the effect of fruquintinib plus anti-PD-1 was verified using a murine syngeneic model of CT26 cells (MSS). The results showed that cotreatment significantly inhibited tumor growth and promote survival time for tumor-bearing mice compared with the single drug alone. In addition, fruquintinib/anti-PD-1 cotreatment decreased angiogenesis, enhanced normalization of the vascular structure, and alleviated tumor hypoxia. Moreover, the combination therapy reprogrammed the immune microenvironment by enhancing chemotactic factor release, increasing CD8+ T cell infiltration and activation, decreasing ration of regulatory T cells, and promoting M1/M2 ratio of macrophage. Finally, the enhanced antitumor effect of fruquintinib/anti-PD-1 cotreatment was significantly reversed in CD8 knockout mice compared with that in the wild-type mice. Our study indicated that combination of fruquintinib and anti-PD-1 could synergistically suppress CRC progression and altered the tumor microenvironment in favor of antitumor immune responses.
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