STAT3 inhibition enhances CDN-induced STING signaling and antitumor immunity.
Pei J1, Zhang Y1, Luo Q1, Zheng W1, Li W1, Zeng X1, Li Q1, Quan J2.
1State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.2State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China. Electronic address: firstname.lastname@example.org.
Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a key regulator in innate immunity and has emerged as a promising drug target in cancer treatment, but the utility of this pathway in therapeutic development is complicated by its dichotomous roles in tumor development and immunity. The activation of the STING pathway and the induced antitumor immunity could be attenuated by the feedback activation of IL-6/STAT3 pathway. Here we reported that STAT3 inhibition significantly enhanced the intensity and duration of STING signaling induced by the STING agonist c-diAM(PS)2. Such sensitization effect of STAT3 inhibition on STING signaling depended on STING rather than cGAS, which was mediated by simultaneously upregulating the positive modulators and downregulating the negative modulators of the STING pathway. Furthermore, the combination treatment with the STAT3 inhibitor and STING agonist markedly regressed tumor growth in syngeneic mice by increasing CD8+ T cells and reducing regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Our work provides a rationale for the combination of STAT3 inhibitors and STING agonists in cancer immunotherapy.
Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.
Immunity; Immunotherapy; STAT3; Tumor microenvironment; cGAS-STING