STING-IRG1 inhibits liver metastasis of colorectal cancer by regulating the polarization of tumor-associated macrophages

Yixuan Liu; Qi Sun; Chengfei Zhang; Min Ding; Cheng Wang; Qian Zheng; Zhijie Ma; Haojun Xu; Guoren Zhou; Xiaoming Wang; Zhangjun Cheng; Hongping Xia

doi:10.1016/j.isci.2023.107376

STING-IRG1 inhibits liver metastasis of colorectal cancer by regulating the polarization of tumor-associated macrophages

iScience. 2023 Jul 13;26(8):107376. doi: 10.1016/j.isci.2023.107376. eCollection 2023 Aug 18.

Authors

Yixuan Liu^{1

2

3}, Qi Sun^{1

2

3}, Chengfei Zhang⁴, Min Ding⁵, Cheng Wang³, Qian Zheng³, Zhijie Ma³, Haojun Xu³, Guoren Zhou⁶, Xiaoming Wang⁷, Zhangjun Cheng², Hongping Xia^{1

2

3}

Affiliations

¹ Department of Pathology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing 210008, China.
² Hepato-Pancreato-Biliary Center, Zhongda Hospital, School of Medicine & Advanced Institute for Life and Health, Southeast University, Nanjing 210009, China.
³ School of Basic Medical Sciences & Key Laboratory of Antibody Technique of National Health Commission & Jiangsu Antibody Drug Engineering Research Center, Nanjing Medical University, Nanjing 211166, China.
⁴ Sir Run Run Hospital, Nanjing Medical University, Nanjing 211166, China.
⁵ Department of Pathology, The Second Affiliated Hospital of Air Force Medical University, Xi'an 710072, China.
⁶ Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institute of Cancer Research, Nanjing 210009, China.
⁷ Department of Hepato-Biliary-Pancreatic Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, China.

Abstract

The liver is the main site of colorectal cancer (CRC) metastasis. Tumor-associated macrophages (TAMs) play a key role in tumor metastasis. Therefore, modulating the function of tumor-associated macrophages is a potential therapeutic strategy to control tumor metastasis. We found in vivo experiments that the activation of STING inhibited CRC liver metastasis in model mice and affected the macrophage phenotype in the tumor microenvironment. Mechanistically, STING affects TAM polarization and regulates macrophage function through IRG1. And STING activates IRG1 to promote the nuclear translocation of TFEB, affecting the ability of macrophages to suppress tumor metastasis.Therefore, this study highlights the critical role of the STING-IRG1 axis on TAM reprogramming and its role in the process of tumor liver metastasis, which may provide a promising therapeutic strategy for CRC liver metastasis.

Keywords: Biological sciences; Immunity; cancer; molecular biology.