Molecular Pathways: Targeting the Stimulator of Interferon Genes (STING) in the Immunotherapy of Cancer

Abstract

Novel immunotherapy approaches are transforming the treatment of cancer, yet many patients remain refractory to these agents. One hypothesis is that immunotherapy fails because of a tumor microenvironment that fails to support recruitment of immune cells, including CD8(+) T cells. Therefore, new approaches designed to initiate a de novo antitumor immune response from within the tumor microenvironment are being pursued. Recent evidence has indicated that spontaneous activation of the Stimulator of Interferon Genes (STING) pathway within tumor-resident dendritic cells leads to type I IFN production and adaptive immune responses against tumors. This pathway is activated in the presence of cytosolic DNA that is detected by the sensor cyclic GMP-AMP synthase (cGAS) and generates cyclic GMP-AMP (cGAMP), which binds and activates STING. As a therapeutic approach, intratumoral injection of STING agonists has demonstrated profound therapeutic effects in multiple mouse tumor models, including melanoma, colon, breast, prostate, and fibrosarcoma. Better characterization of the STING pathway in human tumor recognition, and the development of new pharmacologic approaches to engage this pathway within the tumor microenvironment in patients, are important areas for clinical translation.

Figure 1

Working model of the innate immune sensing of tumors leading to spontaneous T cell responses in vivo. In the tumor microenvironment, tumor-derived DNA (likely released by dead cells, or via acquisition of DNA-containing vesicles) can gain access to the cytosol of intratumoral dendritic cells (DCs). Recognition of cytosolic DNA by cyclic GMP-AMP (cGAMP) synthase (cGAS), and generation of cGAMP, leads to the activation of STING (stimulator of interferon genes). This results in the phosphorylation of tank-binding kinase 1 (TBK1) and subsequent activation, which in turn phosphorylates the transcription factor interferon regulatory factor 3 (IRF3). This activates the transcription of type I interferon (IFN) genes. The STING pathway can be also deliberately stimulated by the use of direct STING agonists, when the compounds are therapeutically administered into the tumor microenvironment. In vivo studies using gene-targeted mice demonstrated a crucial role of STING pathway activation, type I IFN production, and its signaling on the BATF3 (basic leucine zipper transcription factor ATF-like 3) lineage of DCs for spontaneous antitumor T cell responses in vivo and recruitment of effector T cells into the tumor microenvironment. dsDNA, double-stranded DNA.