Enhancing chemosensitivity is one of the largest unmet medical needs in cancer therapy. Cyclic GMP-AMP synthase (cGAS) connects genome instability caused by platinum-based chemotherapeutics to type I interferon (IFN) response. Here, by using a high-throughput small-molecule microarray-based screening of cGAS interacting compounds, we identify brivanib, known as a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor, as a cGAS modulator. Brivanib markedly enhances cGAS-mediated type I IFN response in tumor cells treated with platinum. Mechanistically, brivanib directly targets cGAS and enhances its DNA binding affinity. Importantly, brivanib synergizes with cisplatin in tumor control by boosting CD8⁺ T cell response in a tumor-intrinsic cGAS-dependent manner, which is further validated by a patient-derived tumor-like cell clusters model. Taken together, our findings identify cGAS as an unprecedented target of brivanib and provide a rationale for the combination of brivanib with platinum-based chemotherapeutics in cancer treatment.

增强化学敏感性是癌症治疗中最大的未满足医疗需求之一。环 GMP-AMP 合酶 (cGAS) 将铂类化疗药物引起的基因组不稳定性与 I 型干扰素 (IFN) 反应联系起来。在这里，通过使用基于高通量小分子微阵列的 cGAS 相互作用化合物筛选，我们将被称为血管内皮生长因子受体和成纤维细胞生长因子受体双重抑制剂的布立尼布鉴定为 cGAS 调节剂。Brivanib 显着增强用铂处理的肿瘤细胞中 cGAS 介导的 I 型 IFN 反应。从机制上讲，brivanib 直接靶向 cGAS 并增强其 DNA 结合亲和力。^{重要的是，brivanib 通过增强 CD8 +}在肿瘤控制中与顺铂协同作用T 细胞以肿瘤固有的 cGAS 依赖性方式作出反应，这通过患者来源的肿瘤样细胞簇模型进一步验证。综上所述，我们的研究结果将 cGAS 确定为布立尼布前所未有的靶标，并为布立尼布与铂类化疗药物联合用于癌症治疗提供了依据。