Antiangiogenic agents, generally antibodies or tyrosine-kinase inhibitors that target the VEGF–VEGFR pathway, are currently among the few combination partners clinically proven to improve the efficacy of immune-checkpoint inhibitors (ICIs). This benefit has been demonstrated in pivotal phase III trials across different cancer types, some with practice-changing results; however, numerous phase III trials have also had negative results. The rationale for using antiangiogenic drugs as partners for ICIs relies primarily on blocking the multiple immunosuppressive effects of VEGF and inducing several different vascular-modulating effects that can stimulate immunity, such as vascular normalization leading to increased intratumoural blood perfusion and flow, and inhibition of pro-apoptotic effects of endothelial cells on T cells, among others. Conversely, VEGF blockade can also cause changes that suppress antitumour immunity, such as increased tumour hypoxia, and reduced intratumoural ingress of co-administered ICIs. As a result, the net clinical benefits from antiangiogenic–ICI combinations will be determined by the balance between the opposing effects of VEGF signalling and its inhibition on the antitumour immune response. In this Perspective, we summarize the results from the currently completed phase III trials evaluating antiangiogenic agent–ICI combinations. We also discuss strategies to improve the efficacy of these combinations, focusing on aspects that include the deleterious functions of VEGF–VEGFR inhibition on antitumour immunity, vessel co-option as a driver of non-angiogenic tumour growth, clinical trial design, or the rationale for drug selection, dosing and scheduling.

抗血管生成药物，通常是针对 VEGF-VEGFR 通路的抗体或酪氨酸激酶抑制剂，是目前临床证明可以提高免疫检查点抑制剂 (ICIs) 功效的少数联合药物之一。这种益处已在针对不同癌症类型的关键 III 期试验中得到证明，其中一些试验的结果改变了实践；然而，许多 III 期试验也取得了负面结果。使用抗血管生成药物作为 ICI 的合作伙伴的基本原理主要依赖于阻断 VEGF 的多重免疫抑制作用，并诱导几种不同的血管调节作用，这些作用可以刺激免疫，例如血管正常化导致肿瘤内血液灌注和流量增加，以及抑制原- 内皮细胞对 T 细胞的凋亡作用等。相反，VEGF 阻断也会导致抑制抗肿瘤免疫的变化，例如肿瘤缺氧增加，以及联合给药的 ICI 进入肿瘤内减少。因此，抗血管生成-ICI 组合的净临床效益将取决于 VEGF 信号传导的相反作用与其对抗肿瘤免疫反应的抑制之间的平衡。在本视角中，我们总结了目前已完成的评估抗血管生成剂与 ICI 组合的 III 期试验的结果。我们还讨论了提高这些组合疗效的策略，重点关注包括 VEGF-VEGFR 抑制对抗肿瘤免疫的有害功能、血管共选作为非血管生成性肿瘤生长的驱动因素、临床试验设计或基本原理等方面。用于药物选择、剂量和安排。