Key Points An MSS CRC patient responded rapidly to fruquintinib plus anti–PD-1 therapy. Fruquintinib plus anti–PD-1 treatment significantly inhibited tumor growth in mice. Fruquintinib plus anti–PD-1 treatment led to an antitumor tumor microenvironment. Visual Abstract 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.

中文翻译：

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呋喹替尼联合抗 PD-1 治疗结直肠癌

要点 一名 MSS CRC 患者对呋喹替尼加抗 PD-1 治疗反应迅速。呋喹替尼联合抗 PD-1 治疗显着抑制了小鼠的肿瘤生长。呋喹替尼联合抗 PD-1 治疗导致了抗肿瘤肿瘤微环境。视觉摘要 识别结直肠癌 (CRC) 的有效疗法仍然是迫切的医疗需求，尤其是对于微卫星稳定 (MSS) 表型。在目前的研究中，研究了呋喹替尼联合抗 PD-1 治疗 MSS CRC 的情况。首先，报告了晚期 MSS CRC 病例。在多线治疗失败后，患者在接受呋喹替尼联合抗PD-1治疗后终于实现了快速反应。然后使用 CT26 细胞 (MSS) 的鼠同基因模型验证了呋喹替尼加抗 PD-1 的作用。结果表明，与单独使用单一药物相比，联合治疗显着抑制了荷瘤小鼠的肿瘤生长并延长了存活时间。此外，呋喹替尼/抗 PD-1 联合治疗减少了血管生成，增强了血管结构的正常化，并减轻了肿瘤缺氧。此外，联合疗法通过增强趋化因子释放、增加 CD8+ T 细胞浸润和活化、降低调节性 T 细胞比例和促进巨噬细胞的 M1/M2 比例来重编程免疫微环境。最后，与野生型小鼠相比，呋喹替尼/抗 PD-1 联合治疗增强的抗肿瘤作用在 CD8 敲除小鼠中显着逆转。