Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy
Yujia Chen, Guan-Nan Li, Xian-Jing Li, Lin-Xing Wei, Minjie Fu, Zhou‐Li Cheng, Zhen Yang, Gui‐Qi Zhu, Xudong Wang, Cheng Zhang, Jinye Zhang, Yiping Sun, Hexige Saiyin, Jin Zhang, Wei‐Ren Liu, Wenwei Zhu, Kun‐Liang Guan, Yue Xiong, Yong Yang, Dan Ye, Leilei Chen
Abstract
Immune-responsive gene 1 (IRG1) encodes aconitate decarboxylase (ACOD1) that catalyzes the production of itaconic acids (ITAs). The anti-inflammatory function of IRG1/ITA has been established in multiple pathogen models, but very little is known in cancer. Here, we show that IRG1 is expressed in tumor-associated macrophages (TAMs) in both human and mouse tumors. Mechanistically, tumor cells induce Irg1 expression in macrophages by activating NF-κB pathway, and ITA produced by ACOD1 inhibits TET DNA dioxygenases to dampen the expression of inflammatory genes and the infiltration of CD8 + T cells into tumor sites. Deletion of Irg1 in mice suppresses the growth of multiple tumor types and enhances the efficacy of anti–PD-(L)1 immunotherapy. Our study provides a proof of concept that ACOD1 is a potential target for immune-oncology drugs and IRG1 -deficient macrophages represent a potent cell therapy strategy for cancer treatment even in pancreatic tumors that are resistant to T cell–based immunotherapy.