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Table 2 Characteristics and preclinical applications of different STING agonists

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

[104, 105]

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;

[107, 108]

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

[119, 120]

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

[91, 117, 121,122,123]

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]

  1. FAA, flavone acetic acid; DMXAA, 5,6-dimethylxanthenone-4-acetic acid; CMA, 10-carboxymethyl-9-acridanone; PARPi, PARP inhibitor; CHK1i, CHK1 inhibitor; C11, N-(Methylcarbamoyl)-2-{[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]sulfanyl}-2-phenylacetamide; BNBC, 6-bromo-N-(naphthalen-1-yl)-benzo [d ][1, 3] dioxole-5-carboxamide; DSDP, dispiro diketopiperazine; G10, 4-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo [b]thiazine-6-carboxamide; ABZI, amidobenzimidazole; TNBC: Triple-Negative Breast Cancer; PBMC: Peripheral blood mononuclear cell; i.t.: intratumoral injection; i.p.: intraperitoneal injection; i.v.: intravenous injection