STING Agonists as Cancer Therapeutics

Abstract

The interrogation of intrinsic and adaptive resistance to cancer immunotherapy has identified lack of antigen presentation and type I interferon signaling as biomarkers of non-T-cell-inflamed tumors and clinical progression. A myriad of pre-clinical studies have implicated the cGAS/stimulator of interferon genes (STING) pathway, a cytosolic DNA-sensing pathway that drives activation of type I interferons and other inflammatory cytokines, in the host immune response against tumors. The STING pathway is also increasingly understood to have other anti-tumor functions such as modulation of the vasculature and augmentation of adaptive immunity via the support of tertiary lymphoid structure development. Many natural and synthetic STING agonists have entered clinical development with the first generation of intra-tumor delivered cyclic dinucleotides demonstrating safety but only modest systemic activity. The development of more potent and selective STING agonists as well as novel delivery systems that would allow for sustained inflammation in the tumor microenvironment could potentially augment response rates to current immunotherapy approaches and overcome acquired resistance. In this review, we will focus on the latest developments in STING-targeted therapies and provide an update on the clinical development and application of STING agonists administered alone, or in combination with immune checkpoint blockade or other approaches.

The Proper Administration Sequence of Radiotherapy and Anti-Vascular Agent—DMXAA Is Essential to Inhibit the Growth of Melanoma Tumors

“…The activation of immune cells after DMXAA application is mainly related to the protein STING (stimulator of interferon genes). The pathway associated with the STING protein is a relatively new direction of research in cancer therapy [63]. It is well known that immune cells' activation using STING agonists mediates the innate immune response, which is responsible for the therapeutic effect [21,64].…”

Cytosolic Self-DNA—A Potential Source of Chronic Inflammation in Aging

“…The cGAS-STING signaling in cancer cells is an increasingly recognized and important mechanism connecting genome instability to immune cell infiltration and inflammation in neoplastic malignant tumors [ 210 ]. Subsequently, tumor cells frequently impair cGAS-STING signaling to evade immune surveillance [ 211 , 212 , 213 ]. Thus, agonists are being developed to restore and to enhance cGAS-STING activity and the subsequent antitumor immune response in cancer treatment [ 212 ].…”

“…Subsequently, tumor cells frequently impair cGAS-STING signaling to evade immune surveillance [ 211 , 212 , 213 ]. Thus, agonists are being developed to restore and to enhance cGAS-STING activity and the subsequent antitumor immune response in cancer treatment [ 212 ]. It should be noted, however, that the immune response to cancer cells including the cGAS-STING signaling, is complex and an extensive review of the current state of the field is beyond the scope of this Review.…”

Tanreqing Inhibits LPS-Induced Acute Lung Injury In Vivo and In Vitro Through Downregulating STING Signaling Pathway

“…An increasing number of investigations have shown that STING is involved in various diseases; the activation of STING can develop as cancer therapeutics. However, the activation of STING can also induce inflammatory responses and lead to inflammatory injury ( Amouzegar et al, 2021 ; Decout et al, 2021 ). The activation of STING is associated with inflammatory diseases such as acute pancreatitis, sepsis, and rheumatoid arthritis ( Jeremiah et al, 2014 ; Heipertz et al, 2017 ; Zhao et al, 2018 ; Wang et al, 2019 ).…”