cGAS-STING pathway in oncogenesis and cancer therapeutics

Abstract

The host innate immunity offers the first line of defense against infection. However, recent evidence shows that the host innate immunity is also critical in sensing the presence of cytoplasmic DNA derived from genomic instability events, such as DNA damage and defective cell cycle progression. This is achieved through the cyclic GMP-AMP synthase (cGAS)/Stimulator of interferon (IFN) genes (STING) pathway. Here we discuss recent insights into the regulation of this pathway in cancer immunosurveillance, and the downstream signaling cascades that coordinate immune cell recruitment to the tumor microenvironment to destroy transformed cells through cellular senescence or cell death programs. Its central role in immunosurveillance positions the cGAS-STING pathway as an attractive anti-cancer immunotherapeutic drug target for chemical agonists or vaccine adjuvants and suggests a key node to be targeted in a synthetic lethal approach. We also discuss adaptive mechanisms used by cancer cells to circumvent cGAS-STING signaling and present evidence linking chronic cGAS-STING activation to inflammation-induced carcinogenesis, cautioning against the use of activating the cGAS-STING pathway as an anti-tumor immunotherapy. A deeper mechanistic understanding of the cGAS-STING pathway will aid in the identification of potentially efficacious anti-cancer therapeutic targets. www.oncotarget.com Jackson for editing and providing comments on the manuscript.

Effective delivery of STING agonist using exosomes suppresses tumor growth and enhances antitumor immunity

“…Our data also indicate a superior antitumor effect of iExo STINGa treatment compared with STINGa, and the reduced tumor growth with iExo STINGa was associated with an influx of proliferating CD8 + T cells, in agreement with previous studies reporting antitumor response with STING pathway activation ( 4 , 35 ). Despite being administered intratumorally, iExo STINGa treatment showed an antitumor effect on contralateral, noninjected tumors.…”

“…Dendritic cells (DCs) bridge innate and adaptative response, and DNA released from genomic unstable cancer cells elicits DCs' type I interferon signaling, activating naïve T cells and promoting antitumor responses ( 4 , 5 ). A critical pathway in DCs sensing cytosolic DNA, in part serving as viral infection police, is the stimulator of interferon genes (STING) pathway.…”

“…The STING protein on the endoplasmic reticulum of DCs responds to cGAMP by activating the transcription of type I interferon and cytokines, which in turn activates and primes antigen-specific CD8 + T cells ( 6 , 7 ). In the context of tumors, STING activation can also influence the immune microenvironment by limiting the accumulation of MDSCs and Tregs and by promoting M1-macrophage polarization ( 4 ). Activation of the STING pathway promotes innate and adaptive immune cell infiltration in tumors, but also exerts antitumor effects by triggering apoptosis, inducing autophagy, and suppressing cell cycle progression of cancer cells, and by promoting vascular normalization in endothelial cells ( 8 ).…”

Disruption of DNA polymerase ζ engages an innate immune response

“…Our work suggests that such inhibitors may also induce a cGAS-STING response due to the increased chromosomal instability. Promoting the activation of the cGAS-STING pathway as a way to engage the immune system is being widely explored as a new tool in cancer therapy (Hoong et al, 2020). Given our results, it would be exciting to investigate whether pol z disruption could also engage the innate immune system in a way that could be exploited for cancer treatment.…”

Small Extracellular Vesicles: A Novel Avenue for Cancer Management

“…DNA fragments resulted from chemotherapy are a well-known example of DAMPs. For instance, chromosomal DNA-rich sEVs from cancer cells treated with topotecan activated DCs via the cGAS-STING signaling pathway, thereby inducing cancer cell apoptosis and inhibiting tumor progression ( 213 , 231 , 232 ). Given that these sEVs may promote antitumor immunity, careful selection of DNA-containing sEVs subpopulations is critical.…”