From: Comprehensive elaboration of the cGAS-STING signaling axis in cancer development and immunotherapy
Classification | Characteristics | Application models | Treatment information | Therapeutic effects | References | |
---|---|---|---|---|---|---|
Natural CDN agonists | c-di-GMP | Poor membrane permeability; suitable for various codelivery technologies | Colon cancer (H508 cells); | 50 μM | Inhibits proliferation | |
4 T1 metastatic breast cancer | 15 nmol (i.p.) | 70% tumor regression | ||||
150 nmol (i.p.) | 92% tumor regression | |||||
0.01-2 nmol (i.p.) | Accelerates T-cell response | |||||
3′3′-cGAMP | Higher binding affinity for mSTING than for hSTING | Chronic lymphocytic leukemia; | 10 mg/kg (i.p.) | Leukemia elimination | [106] | |
multiple myeloma | 10 mg/kg (i.p.) | Suppresses growth | ||||
2′3′-cGAMP | Higher affinity for hSTING than its lineage isomers; binds to various STING nucleotide polymorphisms observed in humans; easily degraded by phosphodiesterase; impermeable to the cell membrane | CT26 colon adenocarcinoma; | > 5 mg/kg | Restrains tumorigenesis; | ||
Improves survival rate | ||||||
breast cancer (4 T1-luc); | 2.5 μg/25 μL/dose (i.t.) | Delays tumor growth | ||||
squamous cell carcinomas (mSCC1); | 2.5 μg/25 μL/dose (i.t.) | Delays tumor growth | ||||
colon cancer (CT26); | 2.5 μg/25 μL/dose (i.t.) | Delays tumor growth | ||||
melanoma (B16F10) | 2.5 μg/25 μL/dose (i.t.) | Delays tumor growth | ||||
Synthetic CDN agonists | STINGVAX | Potent in vivo antitumor efficacy in multiple therapeutic models of established cancer | B16 melanoma; | 20-200 μg CDNs (i.t.) | Reduces tumor volume | [104] |
colon carcinoma (CT26); | ||||||
pancreatic carcinoma (Panc02) | ||||||
cGAMP-NPs | Liposomal nanoparticles (NPs) deliver cGAMP intracellularly more effectively than realized with soluble cGAMP | B16F10 melanoma; | i.v. | Creates a tumoricidal state | [108] | |
TNBC | ||||||
Biopolymer scaffolds (c-di-GMP and CAR T cells) | Eradicates tumors more effectively than systemic delivery | Pancreatic cancer | 6 μg c-di-GMP | Tumor regression | [106] | |
c-di-GMP/YSK05-Lip | YSK05 is a lipid that can efficiently deliver c-di-GMP to the cytosol; possesses high fusogenic activity, which enhances endosomal escape | B16F10 mouse melanoma | 3 μg c-di-GMP (i.v.) | Decreases metastasis | [107] | |
2′3′-cGsAsMP | More resistant to degradation by ENPP1; ten-fold more potent at inducing IFN secretion; potential use as a cancer vaccine adjuvant | THP1 monocytes | [116] | |||
ADU-S100 | Improves stability and lipophilicity; higher affinity for hSTING than natural CDN agonists; capable to activate all hSTING variants and mSTING | B16 melanoma; | three 50 mg doses (i.t.) | Durable tumor regression | [117] | |
4 T-1 breast cancer; | three 50 mg doses (i.t.) | Durable tumor regression | ||||
MC26 colon cancer | three 50 mg doses (i.t.) | Durable tumor regression | ||||
IACS-8779 | Stimulates a superior systemic antitumor response than ADU-S100 and cGAMP | B16 melanoma | 10 μg on day 6, 9 and 12 posttumor implantation | Antitumor response | [118] | |
IACS-8803 | ||||||
Non-CDN agonists | FAA | Causes hemorrhagic necrosis; failed in a phase I clinical trial due to species specificity | Murine colon tumors | Extensive tumor rejection | ||
DMXAA | First discovered as a vascular disrupting agent; high affinity for mSTING, with minimal effect on hSTING | Rat mammary carcinoma; | 300 mg/kg (i.p.) | High anticancer potency | ||
B16 melanoma; | 500 μg (i.t.) | Accelerates tumor rejection | ||||
NETs; | 22.5 mg/kg (i.p.) | Inhibits tumor growth | ||||
acute myeloid leukemia; | 450 μg (i.v.) | Inhibits tumor growth | ||||
glioma GL261; | 25 mg/kg (i.p.) | Inhibits tumor growth | ||||
lung cancer | 25 mg/kg (i.p.) | Inhibits tumor growth | ||||
adrenocortical cancer | 22.5 mg/kg (i.p.) | Inhibits tumor growth | ||||
α-Mangostin | Higher affinity for hSTING than for mSTING | THP1 cells | [124] | |||
CMA | Exclusive mSTING agonist; inactive against human cells | HEK 293 T cells; mouse macrophages | Antiviral activity | [125] | ||
Indirect agonists | Radiotherapy | Causes the release of cytosolic DNA fragments; low RT doses decrease TREX1, thus activating STING | MC38 colon cancer; | 20 Gy | Adaptive immune response; | [126] |
HT29 colorectal tumor cells | 6 Gy | induces type III IFNs | [127] | |||
Cisplatin | Forms DNA adducts and inhibits DNA repair | Epithelial ovarian cancer | 11.8 μM | Accumulates T cells | [128] | |
Teniposide | Activates STING; increases MHC expression on the tumor cell surface | B16 melanoma; | Activates DC and T cells | [129] | ||
colon cancer (CT26, MC38) | ||||||
PARPi (Olaparib) | Generates cytoplasmic chromatin fragments with characteristics of micronuclei | ERCC1-deficient NSCLC cells; | Inhibits proliferation | [130] | ||
Brca1-deficient ovarian cancer; | 50 mg/kg/day (i.p.) | Strong T-cell cytotoxicity | [126] | |||
Brca1-deficient TNBC | 50 mg/kg/day (i.p.) | Strong T-cell cytotoxicity | [131] | |||
CHK1i (Prexasertib) | Accelerates DNA double-strand breaks and STING activation | SCLC tumors | 10 mg/kg twice daily | Enhances T-cell recruitment | [132] | |
Small-molecule agonists | C11 | Triggers IRF3/IFN-dependent responses in a STING-dependent manner | THF cells | Blocks replication of alphavirus | [133] | |
BNBC | Induces innate immunity against various viruses and promotes the activation of adaptive immune responses | Primary human fibroblasts and PBMCs | Antiviral activity | [134] | ||
DSDP | Induces proinflammatory cytokines in a STING-dependent manner | Human fibroblasts | Antiviral activity | [135] | ||
G10 | Selectively induces STING-dependent synthesis and secretion of bioactive IFNs; no evidence of binding directly to STING | Human fibroblasts | Antiviral activity | [136] | ||
ABZI | Activates STING in “open” conformation; sub-micromolar levels induce STING activation and IFN production | Colon tumors | 1.5 mg/kg (i.v.) | 80% of a treated group remained tumor free | [52] |