1. Academic Validation
  2. STING activation in macrophages by vanillic acid exhibits antineoplastic potential

STING activation in macrophages by vanillic acid exhibits antineoplastic potential

  • Biochem Pharmacol. 2023 May 19;213:115618. doi: 10.1016/j.bcp.2023.115618.
Man Zhu 1 Xiaoyu Tang 1 Zeren Zhu 1 Zhengyan Gong 1 Wenjuan Tang 1 Yu Hu 1 Cheng Cheng 1 Hongying Wang 1 Ammar Sarwar 1 Yanbin Chen 2 Feng Liu 2 Jian Huo 1 Xuemei Wang 1 Yanmin Zhang 3
Affiliations

Affiliations

  • 1 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.
  • 2 Shaanxi Institute of International Trade & Commerce, Xianyang 712046, China; Shaanxi Buchang Pharmaceutical Co. Ltd, Xi'an 710075, China.
  • 3 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. Electronic address: zhang2008@xjtu.edu.cn.
Abstract

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.

Keywords

Anti-tumor; Apoptosis; Immune activation; Macrophage; STING; Vanillic acid.

Figures
Products
Inhibitors & Agonists
Other Products