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Review
. 2021 Nov 9:12:781032.
doi: 10.3389/fimmu.2021.781032. eCollection 2021.

The Function of cGAS-STING Pathway in Treatment of Pancreatic Cancer

Ghazal Mohseni  1   2 , Juan Li  1 , Abakundana Nsenga Ariston Gabriel  1   2 , Lutao Du  1 , Yun-Shan Wang  1 , Chuanxin Wang  1
Affiliations
Review

The Function of cGAS-STING Pathway in Treatment of Pancreatic Cancer

Ghazal Mohseni et al. Front Immunol. .

Abstract

The activation of stimulator of interferon genes (STING) signalling pathway has been suggested to promote the immune responses against malignancy. STING is activated in response to the detection of cytosolic DNA and can induce type I interferons and link innate immunity with the adaptive immune system. Due to accretive evidence demonstrating that the STING pathway regulates the immune cells of the tumor microenvironment (TME), STING as a cancer biotherapy has attracted considerable attention. Pancreatic cancer, with a highly immunosuppressive TME, remains fatal cancer. STING has been applied to the treatment of pancreatic cancer through distinct strategies. This review reveals the role of STING signalling on pancreatic tumors and other diseases related to the pancreas. We then discuss new advances of STING in either monotherapy or combination methods for pancreatic cancer immunotherapy.

Keywords: cGAS-STING pathway; cytosolic DNA; immunotherapy; pancreatic cancer; type I interferon (IFN).

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Illustrates the cGAS- STING pathway. The cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) functions as an adjuvant for stimulator of interferon genes (STING). cGAS detects the cytosolic DNA and then binds to STING and activates it. The activated STING is translocated to Golgi and stimulates the production of type I IFNs and NF-κB through tank-binding kinase 1 (TBK1)/interferon regulatory factor 3 (IRF3). The type I IFNs binds to the Interferon-α/β receptor (IFNAR) and activates Janus kinase (JAK)- signal transducer and activator of transcription proteins (STAT) pathway. The phosphorylated STAT1 and STAT2 join interferon regulatory factor 9 (IRF9) and make the interferon-stimulated gene factor 3 (ISGF3) complex, which increases the expression of IFN-stimulated genes.
Figure 2
Figure 2
Shows the effect of the cGAS-STING pathway on different types of cells in the pancreas. The cGAS-STING pathway exacerbates acute pancreatitis by increasing tumor necrosis factor-alpha (TNFα) and IFNβ. On the other hand, this pathway regulates the production of Th17, which protects against chronic pancreatitis. The cGAS-STING pathway is also involved in the lipotoxic injury of β cells.
Figure 3
Figure 3
Highlights the relationship between STING and ferroptosis. The excessive amount of iron and Gpx4 reduction can induce ferroptosis and production of 8-OHG, which leads to activation of the STING pathway and infiltration of macrophages during Kras-driven pancreatic cancer. However, when STING binds to mitofusins (MFN1/2) activates mitochondrial fusion, which increases the ferroptosis in pancreatic cancer cells.
See this image and copyright information in PMC

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