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.

针对血管内皮生长因子（VEGF）的治疗性抗体已成为肿瘤治疗的关键方案，但单一疗法的疗效通常受到耐药性和多种血管生成机制的限制。由于补体蛋白在促进癌症进展和血管生成方面的作用，它们正在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。我们生成了结合 VEGFA/PIGF 的人源化可溶性 VEGFR-Fc 融合蛋白 (VID) 和靶向 C3b/C4b 的 CR1-Fc 融合蛋白 (CID)。 VID和CID均与其配体具有良好的亲和力并表现出有效的生物活性。在体外，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在结肠炎相关结直肠癌（CAC）模型和原位4T1乳腺癌模型中具有协同治疗作用。从机械角度来看，联合治疗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 耐药肿瘤和慢性炎症相关肿瘤提供了一种新的治疗策略。