School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta Weststreet, #54, Xi'an, Shaanxi Province 710061, China; State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an Jiaotong University, Xi'an 710061, China.
Shaanxi Institute of International Trade & Commerce, Xianyang 712046, China; Shaanxi Buchang Pharmaceutical Co. Ltd, Xi'an 710075, China.
Biochem Pharmacol. 2023 Jul;213:115618. doi: 10.1016/j.bcp.2023.115618. Epub 2023 May 19.
The host stimulator of interferon genes (STING) signaling pathway is a major innate immune sensing pathway, and the stimulation of this pathway within antigen-presenting cells shows promise in targeting immune-suppressed tumors. Macrophages resident in tumors exhibit anti-inflammatory properties and enhance tumor growth and development. Polarizing such macrophages towards a pro-inflammatory phenotype is an effective strategy for tumor suppression. In the present study, we observed that the STING pathway was inactivated in breast and lung carcinomas, and a positive correlation existed between STING and macrophage markers in these tumors. We found that vanillic acid (VA) could stimulate the STING/TBK1/IRF3 pathway. VA mediated the production of type I IFN and promoted macrophage polarization into the M1 phenotype; this activity was dependent on STING activation. A direct-contact co-culture model and a transwell co-culture model revealed that macrophages with VA-induced STING activation exhibited anti-proliferative effects on SKBR3 and H1299 cells, although a STING antagonist and M2 macrophage-related cytokines alleviated this anti-proliferative effect. Further investigation indicated that phagocytosis and apoptosis-inducing effects were the major mediators of the anti-tumor effect of VA-treated macrophages. Mechanistically, VA promoted the polarization of macrophages to a M1 phenotype via IL-6R/JAK signaling, resulting in enhanced phagocytosis and apoptosis-induction effects. Additionally, STING activation-induced IFNβ production also participated in the apoptosis mediated by VA-treated macrophage in SKBR3 and H1299 cells. Mouse models with 4 T1 tumors confirmed the anti-tumor properties of VA in vivo and revealed the infiltration of VA-induced cytotoxic T cells into the tumors. These data suggest that VA is an effective agonist of STING and provides a new perspective for cancer immunotherapy.
干扰素基因（STING）信号通路的宿主刺激物是主要的先天免疫感应途径，在抗原呈递细胞中刺激该途径显示出靶向免疫抑制肿瘤的潜力。肿瘤中驻留的巨噬细胞表现出抗炎特性，并增强肿瘤的生长和发展。将这些巨噬细胞极化向促炎表型是抑制肿瘤的有效策略。在本研究中，我们观察到 STING 通路在乳腺癌和肺癌中失活，并且在这些肿瘤中 STING 与巨噬细胞标志物之间存在正相关。我们发现香草酸（VA）可以刺激 STING/TBK1/IRF3 途径。VA 介导 I 型 IFN 的产生，并促进巨噬细胞向 M1 表型极化；这种活性依赖于 STING 的激活。直接接触共培养模型和 Transwell 共培养模型显示，具有 VA 诱导的 STING 激活的巨噬细胞对 SKBR3 和 H1299 细胞表现出抗增殖作用，尽管 STING 拮抗剂和 M2 巨噬细胞相关细胞因子减轻了这种抗增殖作用。进一步的研究表明，吞噬作用和凋亡诱导作用是 VA 处理的巨噬细胞抗肿瘤作用的主要介导物。在机制上，VA 通过 IL-6R/JAK 信号促进巨噬细胞向 M1 表型极化，从而增强吞噬作用和凋亡诱导作用。此外，STING 激活诱导的 IFNβ 产生也参与了 VA 处理的巨噬细胞在 SKBR3 和 H1299 细胞中的凋亡。具有 4T1 肿瘤的小鼠模型证实了 VA 在体内的抗肿瘤特性，并揭示了 VA 诱导的细胞毒性 T 细胞浸润到肿瘤中。这些数据表明 VA 是 STING 的有效激动剂，为癌症免疫治疗提供了新视角。
