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  3. 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.
PMID: 37211172 DOI: 10.1016/j.bcp.2023.115618
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.

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