Table 2.

The inhibitors and agonists of the cGAS-STING pathway.

Target	Agents	Function or property	Species specificity	Advantage	Disadvantage	Application model	Treatment effect	Ref
cGAS inhibitors	AMDs	Blocking dsDNA/cGAS binding	Human and mouse cGAS	Widely used with a strong safety profile	-	Trex1-/- mouse model	Effective for the treatment of AGS mice	[87]
	EGCG	Disrupting cGAS activation	Human and mouse cGAS	Specifically inhibit inflammation caused by cGAS activation	Effect of EGCG on cGAS activity is clearly dependent on G3BP1	AGS patient cells and AGS mouse model	Effective in treating cGAS-mediated autoinflammation	[139]
	Aspirin	Inhibiting cGAS by acetylation	Human and mouse cGAS	Widely used with a strong safety profile	-	AGS patient cells and AGS mouse model	Effective in treating AGS and potentially other DNA-mediated autoimmune diseases	[140]
	RU.521	Occupying the catalytic site of cGAS	Mouse cGAS	Selective inhibition of cGAS dsDNA-dependent enzymatic activity in vitro and in cells	Poor inhibitor of recombinant human cGAS	AGS mouse model	Suppressing type I IFN expression	[141]
	G140, G150	Inhibiting cGAS activity	Human cGAS	Specific and potent small-molecule inhibitors for human cGAS	The utility for therapeutic treatment of cGAS-related human diseases is uncertain	Human monocytic THP1 cells and mouse macrophage RAW 264.7 cells	Inhibiting dsDNA-induced cGAS activity	[142]
	PAH	Inhibiting cGAS activity	Human and mouse cGAS	No side effects and toxicity with biological safety in vivo	Inhibitory mechanisms are uncertain	AGS mouse model	Ameliorating self-DNA-induced autoinflammatory responses	[143]
	Compound 25	Inhibiting cGAS activity	Human and mouse cGAS	Superior in vivo anti-inflammatory effects	Structural optimization is needed to achieve higher potency	Lipopolysaccharide-induced mouse model	Ihibiting the dsDNA-induced phosphorylation of STING/TBK1/IRF3 signaling and the mRNA expression of ISGs	[144]
	A151	Competing with DNA	Mouse cGAS	Into the damaged brain parenchyma from the blood	-	Ischemic mouse brains model	Protecting against brain damage and improving neurodeficits	[145]
STING inhibitors	Compound 18	Competing with cGAMP	Human STING	Good oral exposure and slow binding kinetics	-	Human monocytic THP1 cells	Inhibiting cGAMP-induced IFNβ production	[146]
	Astin C	Blocking IRF3 recruitment onto the STING	Human and mouse STING	Well-tolerated compound with minimal cytotoxic side effects	The in vivo effectiveness is uncertain	Trex1-/- BMDMs cells and Trex1-/- mouse model	Inhibiting the expression of type I IFN and pro-inflammatory cytokines and alleviating the autoinflammatory responses	[147]
	NO2-FA	Inhibiting STING palmitoylation	Human and mouse STING	Natural antiinflammatory mediators	Not yet used in clinical practice	Fibroblasts from SAVI patients	Inhibiting production of type I IFN	[148]
	C-178, C-176	Inhibiting STING palmitoylation	Mouse STING	In vivo inhibitory capacity is not limited by the short serum half-life	Low affinity to human STING	Trex1-/- mouse model	Amelioration of various signs of systemic inflammation	[149]
	C-170, C-171, H-151	Blocking palmitoylation-induced clustering of STING	Human and mouse STING	Highly potent and selective small-molecule inhibitor	-	Trex1-/- mouse model	Reducing systemic cytokine responses	[149]
	SN-011	Blocking CDN binding and STING activation	Human and mouse STING	Potent and selective inhibitor with high affinity and specificity	-	Trex1-/- mouse model	Ameliorating autoimmune pathology and preventing death	[150]
STING agonists	DMXAA	Non-CDNs	Mouse STING	Potent and specific therapeutic effect on mice	Lacking the ability to activate human STING	Mouse xenotransplantation models	Induction of cytokines and disrupting tumor vascularization	[151]
	CMA	Non-CDNs	Mouse STING	Potent and specific therapeutic effect on mice	Lacking the ability to activate human STING	Mouse macrophages	Inducing IRF3 phosphorylation and Ifnb mRNA translation	[152]
	c(di-GMP)	CDNs	Mouse STING	Mobilizing abscopal immunity when combined with checkpoint modulation	Low affinity to human STING	Bilaterally-implanted TRAMP-C2 tumors mouse model	Mediating regression of injected tumors	[153]
	3'3'-cGAMP	CDNs	Mouse STING	More efficient than DMXAA in activating STING	-	Chronic lymphocytic leukemia and multiple myeloma mouse model	Inducing apoptosis and tumor regression	[154]
	ML RR-S2 CDA	CDNs	Human and mouse STING	Activating all human and mouse STING alleles	Intratumor injection is necessary to achieve maximal therapeutic effect	4T-1 colon or CT26 mammary carcinomas mouse model	Inducing tumor regression and resistant to the same tumor cell line	[103]
	ABZI	Non-CDNs	Human and mouse STING	Intravenous administration can induce adaptive CD8 T cell response in vivo	-	Syngeneic colon tumours mouse model	Strong anti-tumour activity with complete and lasting regression of tumours	[155]
	STING-LNP	Non-CDNs	Mouse STING	Efficiently delivered the STING agonist to the cytoplasm	-	B16-F10-luc2 lung metastatic mouse model	Increasing the expression of CD3, CD4, PD-1 and IFN in lung metastases	[156]
	MSA-2	Non-CDNs	Human and mouse STING	Favorable activity and tolerability profiles	-	MC38 syngeneic tumors mouse model	Inducing tumor regressions	[157]
	PC7A	Non-CDNs	Human and mouse STING	Polyvalent STING agonist with prolonged cytokine expression	-	MC38 and TC-1 tumour models	Notably extended the survival	[158]
	SR-717	Non-CDNs	Human and mouse STING	Substantial efficacy without considerable toxicity	-	B16.F10 melanomas mouse model	Reduction in tumor growth and the increased survival	[159]

cGAS, cyclic guanosine monophosphate (GMP)- adenosine monophosphate (AMP) synthase; cGAMP, cyclic guanosine monophosphate-adenosine monophosphate; STING, stimulator of interferon genes; IFN, interferon; TBK1, TANK-binding kinase 1; IRF3, interferon regulatory factor 3; ISG, interferon stimulated gene; AMDs: antimalarial drugs; EGCG: epigallocatechin gallate; PAH: perillaldehyde; BMDMs: bone marrow-derived macrophages; SAVI: STING-associated vasculopathy with onset in infancy; CDN: cyclic dinucleotide; ABZI: amidobenzimidazole.