STING Agonists as Cancer Therapeutics.

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.