Therapeutic antibodies targeting vascular endothelial growth factor (VEGF) have become a critical regimen for tumor therapy, but the efficacy of monotherapy is usually limited by drug resistance and multiple angiogenic mechanisms. Complement proteins are becoming potential candidates for cancer-targeted therapy based on their role in promoting cancer progression and angiogenesis. However, the antitumor abilities of simultaneous VEGF and complement blockade were unknown. We generated a humanized soluble VEGFR-Fc fusion protein (VID) binding VEGFA/PIGF and a CR1-Fc fusion protein (CID) targeting C3b/C4b. Both VID and CID had good affinities to their ligands and showed effective bioactivities. In vitro, angiogenesis effects induced by VEGF and hemolysis induced by complement were inhibited by VID and CID, respectively. Further, VID and CID confer a synergetic therapeutic effect in a colitis-associated colorectal cancer (CAC) model and an orthotopic 4T1 breast cancer model. Mechanically, combination therapy inhibited tumor angiogenesis, cell proliferation, and MDSC infiltration in the tumor microenvironment and promoted tumor cell apoptosis. Our study offers a novel therapeutic strategy for anti-VEGF-resistant tumors and chronic-inflammation-associated tumors.

靶向血管内皮生长因子（VEGF）的治疗性抗体已成为肿瘤治疗的关键方案，但单一治疗的疗效通常受到耐药性和多种血管生成机制的限制。补体蛋白基于其在促进癌症进展和血管生成中的作用，正成为癌症靶向治疗的潜在候选者。然而，同时VEGF和补体阻断的抗肿瘤能力尚不清楚。我们生成了人源化的可溶性VEGFR-Fc融合蛋白（VID），结合VEGFA / PIGF和靶向C3b / C4b的CR1-Fc融合蛋白（CID）。VID和CID都对它们的配体具有良好的亲和力，并显示出有效的生物活性。体外VID和CID分别抑制VEGF诱导的血管生成作用和补体诱导的溶血作用。此外，VID和CID在结肠炎相关的大肠癌（CAC）模型和原位4T1乳腺癌模型中具有协同治疗作用。在机械上，联合疗法抑制肿瘤微环境中的肿瘤血管生成，细胞增殖和MDSC浸润，并促进肿瘤细胞凋亡。我们的研究为抗VEGF耐药的肿瘤和慢性炎症相关的肿瘤提供了一种新颖的治疗策略。