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STING Agonists as Cancer Therapeutics
Afsaneh Amouzegar1, Manoj Chelvanambi2, Jessica N Filderman2
1Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
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.
Insights
The cGAS/stimulator of interferon genes (STING) pathway is crucial for anti-tumor immunity. New STING agonists and delivery systems show promise for enhancing cancer immunotherapy responses and overcoming resistance.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Lack of antigen presentation and type I interferon signaling are biomarkers for non-T-cell-inflamed tumors and clinical progression in cancer immunotherapy.
- The cGAS/stimulator of interferon genes (STING) pathway, a cytosolic DNA-sensing pathway, is implicated in anti-tumor immune responses, including type I interferon activation and modulation of tumor vasculature.
- The STING pathway also supports adaptive immunity through tertiary lymphoid structure development.
Purpose of the Study:
- To review the latest developments in STING-targeted cancer therapies.
- To provide an update on the clinical development and application of STING agonists.
- To explore the potential of STING agonists in combination with other immunotherapies.
Main Methods:
- Review of pre-clinical studies on the STING pathway in cancer.
- Analysis of clinical trial data for STING agonists.
- Evaluation of novel delivery systems for STING agonists.
Main Results:
- First-generation intra-tumor delivered cyclic dinucleotides showed safety but limited systemic activity.
- Development of more potent and selective STING agonists is ongoing.
- Novel delivery systems aim for sustained inflammation in the tumor microenvironment.
Conclusions:
- STING agonists hold potential to augment response rates to current immunotherapies.
- STING-targeted therapies may overcome acquired resistance to cancer immunotherapy.
- Combination strategies involving STING agonists are being investigated to improve clinical outcomes.
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