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.
Highlights
When functioning properly, the immune system protects the body against disease and pathogenic attack
Regardless, because anaplastic lymphoma kinase (ALK) fusion genes are associated with several types of cancer and these findings suggest a possible role for ALK in cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon (IFN) genes (STING) signaling, the relationship between ALKEGFR-AKT and components of the STING pathway ought to be thoroughly examined with further studies
Considering the differential expression of STING in various cell types, it is reasonable to question whether the www.oncotarget.com use of STING ligands will be effective in the treatment of cancer
Summary
The immune system protects the body against disease and pathogenic attack. These cancer cells transfer cGAMP— produced by cGAS in response to tumor cytosolic DNA—to astrocytes by establishing gap junctions, thereby activating STING and inducing type I IFN and TNFα expression [79]. Activation of the cGAS-STING pathway is associated with the presence of various inducers of senescence, including oxidation, ionizing radiation, cell cycle inhibition (CDK4 inhibitors, such as palbociclib), and DNA damage (cytotoxic agents, such as etoposide) [1, 52].
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