STING activation in macrophages by vanillic acid exhibits antineoplastic potential

Man Zhu; Xiaoyu Tang; Zeren Zhu; Zhengyan Gong; Wenjuan Tang; Yu Hu; Cheng Cheng; Hongying Wang; Ammar Sarwar; Yanbin Chen; Feng Liu; Jian Huo; Xuemei Wang; Yanmin Zhang

doi:10.1016/j.bcp.2023.115618

STING activation in macrophages by vanillic acid exhibits antineoplastic potential

Biochem Pharmacol. 2023 Jul:213:115618. doi: 10.1016/j.bcp.2023.115618. Epub 2023 May 19.

Authors

Man Zhu¹, Xiaoyu Tang¹, Zeren Zhu¹, Zhengyan Gong¹, Wenjuan Tang¹, Yu Hu¹, Cheng Cheng¹, Hongying Wang¹, Ammar Sarwar¹, Yanbin Chen², Feng Liu², Jian Huo¹, Xuemei Wang¹, Yanmin Zhang³

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents* / metabolism
Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Humans
Lung Neoplasms* / metabolism
Macrophages
Mice
Phagocytosis
Vanillic Acid / metabolism
Vanillic Acid / pharmacology
Vanillic Acid / therapeutic use

Substances

Antineoplastic Agents
Vanillic Acid