Table 2.

STING-targeting compounds in pre-clinical stage.

Agent	Structure/Properties	Route of Delivery	Tumor Model	Findings	References
Cyclic dinucleotide (CDN)
JNJ-67544412 (JNJ-4412)	Cyclic dinucleotide, Potently binds to all major human STING alleles	Intratumoral	Subcutaneous syngeneic murine tumor models	-Tumor regression, induction of proinflammatory cytokines such as IFN-α, IFN-β, IP-10, TNF-α, IL-6 and MCP-1 in tumor and plasma, inhibition in growth of contralateral tumors. -Enhanced dose-dependent efficacy when combined with anti-PD1.	[84]
BI-STING	Mimics natural STING ligand	Intratumoral	Subcutaneous syngeneic murine tumor models	-Single dose of intratumoral BI-STING results in transient increase in cytokine levels, dose-dependent local tumor control. No tumor developed upon re-challenge. -Tumor control improved when combined with anti-PD1 -ELISPOT: higher number of immunospots in splenocytes from BI-STING-treated animals showing induction of tumor specific immune response.	[77]
3′3′-cyclic 3′3′-cAIMP	Cyclic dinucleotide	Not specified	Mouse model of mutagen-induced hepatocellular carcinoma	-Treatment of mice after HCC development efficiently reduced tumor size. -Initiation of treatment at later stage of disease development resulted in regression of the majority of tumors, but new treatment-unresponsive tumors were detected.	[85]
GSK532	Cyclic dinucleotide	Intratumoral	CT26 murine syngeneic model	-Strong anti-tumor effect in both the injected and uninjected tumors. -Cured mice were resistant to re-challenge with the same tumor cell line.	[86]
Non-CDN Agonists
Ryvu’s agonists	Selective non-nucleotide, non-macrocyclic, small molecule compounds, potential for systemic administration	Not specified	CT26 murine syngeneic model	-Dose-dependent upregulation of STING-dependent pro-inflammatory cytokines. -Complete tumor remission and development of immunological memory against cancer cells.	[87]
GF3-002	Novel low-molecular-weight organic molecule, not based on a CDN	In vitro	In vitro assays	-Confirmed binding to WT STING and production of IFN-β after treatment of dendritic cells with GF3-002.	[88]
Selvita agonists	Selective non-nucleotide, non-macrocyclic, small molecule compounds, structurally unrelated to known CDNs, tunable properties with enhanced plasma stability and permeability, potential for systemic administration	In vitro	In vitro assays	-Induction of cytokine responses (IFN-β, TNF-α) in human PBMC, human monocyte derived macrophage, and human DCs with various STING haplotypes including refractory alleles. -Induction of pro-inflammatory cytokine profile and up-regulation of the maturation markers on human APCs.	[89]
TTI-10001	Non-CDN small molecule STING agonist	Intratumoral	Multiple syngeneic murine tumor models	-Well-tolerated in vivo; results in increased expression of pro-inflammatory cytokines, and anti-tumor activity.	[90]
JNJ-‘6196	Next-generation STING agonist; binds to STING with weaker affinity and a faster off rate, but more potent than other CDNs in activating dendritic cells	Intravenous	Murine tumor models (not specified)	-Eliminates bilateral tumors, and provides immunity to further re-challenge. -Increases the effectiveness of checkpoint inhibitors, turning a PD-1 resistant model into a responsive model.	[91]
CRD5500	Next-generation small molecule STING agonist. Activates all five common human STING variants. Delivery via different routes (IV or SC) or as an antibody drug conjugate	Intravenous, subcutaneous, Antibody-drug conjugate (ADC) with Trastuzumab	CT26 syngeneic murine model	-In vitro: causes maturation of hDCs and the release of innate and adaptive inflammatory cytokines such as IFN-β and TNF-α. -In vivo administration (IT or systemically): tumor regression in CT26 syngeneic tumors containing human STING.	[92]
CS-1018, CS-1020 and CS-1010	STING agonists with higher potency in activating mouse and human STING variants than natural ligand cGAMP	Intratumoral	B16F10 and MC38 murine tumor models	-All compounds showed dose-dependent anti-tumor activity in MC38 or B16F10 syngeneic models. -Tumor-free treated mice developed tumor specific immunologic memory in MC38 murine model.	[93]
MSA-1	Novel STING agonist with higher potency in activating STING protein than cGAMP	Intratumoral	MC38 syngeneic tumors, CT26 and B16-F10 tumor models	-Complete responses observed in 100% of MC38 tumors. -Restoration of T cell responses (in serum and tumors) of mice with anti-PD1 unresponsive tumors when combined with anti-PD1.	[94]
ALG-031048	Novel STING agonist with high potency and superior stability	Intratumoral, Subcutaneous	Syngeneic CT26 colorectal, B16F10 melanoma, and Hepa1–6 HCC models	-Tumor regression in 90% of mice bearing CT26 tumors (vs. 44% with ADU-S100). Treated mice were resistant to tumor development after re-challenge. -Mean tumor regression of 88% in HCC tumor-bearing mice vs. 72.4% regression with anti-PD1 antibody. -Dose-dependent increase in plasma levels of IFN-β1, IFN-γ, TNF-α, IL-6, MIP-1α and MCP-1 -Subcutaneous ALG-031048 improved anti-tumor efficacy of anti-PDL-1 agent, atezolizumab.	[95]
Macrocyclic STING Agonist
E7766	Macrocyclic STING agonist with superior in vitro activity against all major human STING genotypes, chemical and metabolic stability, conferred by conformational rigidity of the unique macrocycle bridge	Intravesical, Intratumoral	Murine anti-PD1 insensitive NMIBC tumor models, subcutaneous tumor models	-Intravesical: dose-dependent anti-tumor effect vs. anti-PD1 which was ineffective. Tumor-free animals rejected re-challenge of same tumor cell line. Activation of IFN pathway, T cell infiltration, NK activity, induction of IFN-β and CXCL10 inside the bladder cavity and in the urine. -Intratumoral: single IT injection led to complete regression or significant tumor growth delay.	[78,80]
ENPP1 Inhibitor
SR-8541A	Small molecule ENPP1 inhibitor	In vitro	In vitro assays	-Stimulates the migration and infiltration of immune cells (PBMC) into cancer spheroids, increases expression of IFN-β, ISG15 and CXCL10. -ENPP1 CRISPR knockout cell models confirmed that the drug effect is ENPP1-dependent.	[96]
SR-8314	Analog of SR-8291 (a highly selective ENPP1 inhibitor)	Intraperitoneal	Syngeneic murine tumor model	-Increase in gene expression of IFN-β, ISG15 and CXCL10 and secretion of IFN-β in SR-8314-treated THP1 cells. -Anti-tumor activity, increase in CD3+, CD4+ and CD8+ T cells in both SR-8314 and SR-8291-treated tumors, decrease in tumor-associated macrophages in SR-8314-treated tumors.	[97]
Orally available ENPP1 inhibitors	Small molecule compounds with strong binding affinity towards ENPP1	In vitro	In vitro assays	-Specific and high binding affinity to ENPP1 with no effect on other members of the ENPP family, activation of STING pathway. -One of lead compounds is currently under investigation for ADME-Tox, PK and efficacy.	[98]
MV-626	Selective ENPP1 inhibitor with 100% oral bioavailability	Intraperitoneal	Panc02-SIY and MC38 murine tumor models	-Therapeutic doses were well tolerated in mice, without toxicity or clinically significant increases in systemic cytokine levels. -Systemic MV- 626 monotherapy caused tumor growth delay. MV-626 plus radiation therapy significantly increased overall survival.	[99]
Novel Delivery Systems
Antibody drug conjugates (ADC)	STING agonist ADCs	Intravenous	Multiple xenograft and syngeneic murine models	-100-fold more potency in inducing inflammatory cytokine expression compared to free agonist. -Inflammatory cytokines were tumor localized while systemic levels remained low. -Single IV injection of targeted STING ADC in tumor-bearing mice significantly inhibited tumor growth compared to systemically injected diABZI.	[100]
ONM-500 nanovaccine	Novel pH-sensitive polymer that forms an antigen-encapsulating nanoparticle and functions both as a carrier for antigen delivery to DCs and as an adjuvant, activating the STING pathway	Subcutaneous	TC-1 cervical cancer murine model	-Effective binding to human STING protein. -Effective delivery of antigens in vivo to LNs to elicit an antigen-specific CTL response. -ONM-500 nanovaccine containing full-length E6/E7 protein resulted in 100% overall survival of TC-1 bearing mice at 55 days. -Long-term antigen-specific anti-tumor memory response in re-challenge study.	[101]
Neoantigen nanovaccine	Redox-responsive neoantigen-polymer conjugates and a STING agonist DMXAA	Subcutaneous	B16-F10 melanoma murine model	-Nanovaccine combined with anti-PD1 treatment led to 50% survival rate on day 38, compared to 20% in mice receiving non-formulated neoantigen peptides.	[102]
exoSTING	Engineered exosome therapeutic that delivers STING agonist to tumor resident APCs	Intratumoral	Checkpoint refractory B16-F10 melanoma murine model	-exoSTING is retained within the injected tumor, and does not induce systemic cytokine production. -exoSTING treatment results in significant induction of PD-L1 expression. In combination with PD1 checkpoint blockade, exoSTING shows enhanced anti-tumor efficacy over high-dose free STING agonist.	[103,104]
STACT-TREX1	Inhibitory microRNA to TREX1, introduced into the STACT strain.	Intravenous	CT26 and MC38 colon carcinoma models, and B16-F10 melanoma model	-Tumor-specific colonization of STACT-TREX1, immune correlates consistent with STING activation and CD8+ T-cell-dependent immune response. -Potent tumor growth inhibition and complete tumor regressions with STACT-TREX1 monotherapy. Immunity to tumor re-challenge	[82,83]
STING-NPs	Liposomal nanoparticles (NPs) to deliver the STING agonist, cGAMP	Intravenous	Basal-like triple-negative breast cancer (TNBC) murine model	-cGAMP-NPs accumulate within macrophages at the tumor, induce M2 to M1-like phenotype, MHC and co-stimulatory molecule expression, enhanced CD4+ and CD8+ T cell infiltration, and tumor apoptosis. -Effective tumor suppression achieved in anti-PD-L1 non-responsive tumors. -Induction of durable anti-tumor T cell responses and prevention of secondary tumor development.	[105]