STING pathway agonism as a cancer therapeutic

Abstract

The fact that a subset of human cancers showed evidence for a spontaneous adaptive immune response as reflected by the T cell‐inflamed tumor microenvironment phenotype led to the search for candidate innate immune pathways that might be driving such endogenous responses. Preclinical studies indicated a major role for the host STING pathway, a cytosolic DNA sensing pathway, as a proximal event required for optimal type I interferon production, dendritic cell activation, and priming of CD8+ T cells against tumor‐associated antigens. STING agonists are therefore being developed as a novel cancer therapeutic, and a greater understanding of STING pathway regulation is leading to a broadened list of candidate immune regulatory targets. Early phase clinical trials of intratumoral STING agonists are already showing promise, alone and in combination with checkpoint blockade. Further advancement will derive from a deeper understanding of STING pathway biology as well as mechanisms of response vs resistance in individual cancer patients.

Chemotherapy induced immunogenic cell death alters response to exogenous activation of STING pathway and PD-L1 immune checkpoint blockade in a syngeneic murine model of ovarian cancer

“…Activation of the cGAS-STING pathway, via direct (STING agonist, oncolytic virus) and indirect (radiation, PARP inhibitors) approaches, is an emerging immune adjuvant treatment approach 8, 11 . With several promising pre-clinical findings across an array of cancer models, recent reports including ours have confirmed the immune sensitizing effect of STING pathway activation thus improving response to conventional chemotherapy and novel ICB 12 .…”

“…We demonstrated that a non-inflamed pre-existing T helper type I tumor immune microenvironment (TIME), decreased expressions of type I interferon (IFN1) genes and STAT1 protein, low density of TILs associated with poor response to chemotherapy 10 . Strategies attempting to transform these immunologically cold tumors to hot, thus improving therapeutic response through IFN1 activation, have recently garnered tremendous interest across solid tumours 8, 11 .…”

“…One such example is using immune activating agents, including those that activate (cGAS)-Stimulator of Interferon Genes (STING) pathway (Figure 1A). Activation of STING pathway primarily occurs via cytosolic nucleic acid sensing that leads to increased production of IFN induced genes, specifically the TIL recruiting CXCR3 binding chemokines, CXCL9/10/11 and CCL5 11–13 . Supporting this hypothesis, we previously reported that response to platinum chemotherapy can be improved via incorporating STING agonist post carboplatin chemotherapy.…”

When STING Meets Viruses: Sensing, Trafficking and Response

“…It is also believed that STING agonists might be used in antiviral therapies. One of the potential advantages of these new molecules is that they can be transported through blood ( 186 ). This new immunotherapy drug greatly enhanced the adaptive immune function.…”

Mitochondrial DNA: A Key Regulator of Anti-Microbial Innate Immunity

“…The STING pathway has been shown to mediate protective immune defense against infection through a wide range of DNA comprising microbial pathogens. The mitochondrial DNA is similar to that of microbial DNA, and has attained great attention as a mediator of innate immunity via the STING pathway [49,50]. STING protein is activated by direct interaction with cytosolic DNA, which is usually derived from intracellular viruses or bacteria or cyclic GMP-AMP synthetase and so on.…”