P1, N=5, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting | N=140 --> 5 | Trial completion date: Feb 2028 --> Mar 2025 | Trial primary completion date: Feb 2027 --> Mar 2025

P1, N=61, Completed, invoX Pharma Limited | Active, not recruiting --> Completed | N=146 --> 61 | Trial completion date: Dec 2024 --> Jul 2024 | Trial primary completion date: Dec 2024 --> Jul 2024

The therapeutic effect of various nanohybrids were validated in the mice with spontaneous tumor in the colorectal area and tumor-bearing mice, which lead to the increase of ferroptosis, the activation of STING signaling pathway, and the repolarization of macrophages. Collectively, the cGAMP and IPI-549 co-loaded nanohybrids effectively reshaped the tumor immune microenvironment, and exhibited prominent treatment effect of anti-colorectal cancer in vitro, patient-derived organoids, and in vivo.

The combination of EXO-loaded microneedles with FLASH radiotherapy resulted in minimal systemic side effects, attributed to precise drug delivery and radioprotection conferred by FLASH. Altogether, the strategic design of EXO-loaded microneedles holds promise for enhancing MSA-2 delivery, thereby mitigating the radioresistant tumor microenvironment through STING cascade activation-mediated immunotherapy, consequently optimizing the outcomes of FLASH radiotherapy.

Ongoing research and innovation are essential to overcoming these hurdles. STING agonists could play a transformative role in cancer treatment, particularly for patients with hard-to-treat malignancies, by harnessing the body's immune system to target and eliminate cancer cells.

Our results suggest that STING agonists may be able to work indirectly in MCC via signaling through immune and stromal cells in the TME, and may not necessarily need STING expression in the cancer cells. This approach may be particularly effective in tumors that are already infiltrated by inflammatory cells in the TME but are evading immune detection via HLA-I downregulation.

Further, dendritic cells mature, as well as T lymphocyte infiltrate, both of which favor tumor eradication. Therefore, cancer immunotherapy is optimized by novel PSAs delivered by erythrocyte efferocytosis-mimicking delivery pattern.

P2, N=51, Active, not recruiting, ImmuneSensor Therapeutics Inc. | Recruiting --> Active, not recruiting

P2, N=6, Terminated, ImmuneSensor Therapeutics Inc. | N=46 --> 6 | Trial completion date: Feb 2026 --> Sep 2024 | Recruiting --> Terminated | Trial primary completion date: Nov 2025 --> Sep 2024; Slow enrollment.

P1, N=36, Recruiting, University of Maryland, Baltimore

Furthermore, SR717 was found to stimulate the production of anti-viral molecules and trigger the activation of the signaling cascade known as the stimulator of interferon genes (STING) pathway, which contributed to hindering the reproduction of viruses by a certain margin. Collectively, these results indicate that SR717 is capable of inhibiting PRRSV infection in vitro and may have potential as an antiviral drug against PRRSV.

This study underscores the potential of HSA-based nanoparticles for the targeted delivery of STING agonists, effectively enhancing antitumor immunity and improving cancer immunotherapy outcomes. SH-NPs offer a promising solution to the limitations of current STING agonists in clinical settings.

P1, N=18, Terminated, GlaxoSmithKline | Active, not recruiting --> Terminated; The protocol was terminated on the basis of a reprioritization of organizational allocation of resources for clinical research programs.

In this study, we synthesized M-Au@RGD-NM loading MSA-2. Following characterization, we found that RT-based M-Au@RGD-NM treatment achieved good antitumor effects, tumor RT enhancement, and induction of an immune response via STING activation.

As a consequence, the HTCS could achieve photodynamic multiple immunotherapy for melanoma. This work demonstrates multifunctional nanoparticles that efficiently inhibit tumors by PDT and reversing their immunosuppression to realize a versatile therapeutic strategy.

P2, N=20, Not yet recruiting, University of Texas Southwestern Medical Center

Simultaneously, the released Mn2+ acted as a STING agonist promoting dendritic cell maturation, IFN-β production, and proliferation of T cells. Ultimately, this albumin based co-loaded sonosensitizer and STING agonist demonstrated promising potential for advancing tumor treatment.

cGAMP-LNP exhibited promising antitumor activity in the syngeneic mouse model of pancreatic cancer. The LNP platform shows promise for delivering exogenous 2'3'-cGAMP or its derivatives in cancer therapy.

Vilanterol plus the STING agonist sensitised PDAC to CLDN18.2 BiTEs and augmented efficacy as a potential novel strategy.

This study evaluated whether combining a cationic plant-derived nanoparticle adjuvant (Nano-11) with the clinically tested STING agonist ADU-S100 (MIW815) could stimulate anticancer immunity by intradermal vaccination...Therapeutic vaccination with NanoST increased mouse survival by inhibiting B16-OVA tumor growth, and this effect was further enhanced by PD-1 checkpoint blockade. Our study provides a strong rationale for developing NanoST as an adjuvant for intradermal vaccination and next-generation preventative and therapeutic cancer vaccines by STING-targeted activation.

P1, N=204, Recruiting, Ono Pharmaceutical Co. Ltd

Together, our data indicate that targeting a STING agonist to PV TAMs could be used to extend the treatment window for ADT in prostate cancer.

P1, N=146, Active, not recruiting, invoX Pharma Limited | Recruiting --> Active, not recruiting | Trial completion date: Mar 2027 --> Dec 2024 | Trial primary completion date: Mar 2027 --> Dec 2024

P1, N=97, Active, not recruiting, GlaxoSmithKline | Trial primary completion date: Mar 2025 --> Apr 2024

P1, N=140, Terminated, Merck Sharp & Dohme LLC | Completed --> Terminated; Business Reasons

P1, N=35, Recruiting, Actym Therapeutics, Inc. | Not yet recruiting --> Recruiting

Moreover, the immunotherapy was enhanced was enhanced mild photothermal therapy (PTT) of BPQDs platform, producing enough T cells to eliminate tumors and prevent tumor recurrence. This work facilitates further research on targeted delivery of small-molecule immune drugs to enhance the development of clinical immunotherapy.

Interestingly, flow cytometry analyses suggested that the YSK12-LNPs were more likely to activate natural killer cells and M1 macrophages, while the MC3-LNPs were more likely to activate CD8+ T cells. Our data suggest that different antitumor immune response mechanisms may operate depending on the characteristics and distribution of the LNPs.

Although the combination with a STAT3 inhibitor did not further enhance STING agonist activity, the addition of anti-PD-1 antibodies to 8803 treatment enhanced survival in an immune checkpoint blockade-responsive glioma model. In summary, 8803 as a monotherapy demonstrates marked in vivo therapeutic activity, meriting consideration for clinical translation.

P1, N=30, Recruiting, Sichuan Kelun Pharmaceutical Research Institute Co., Ltd. | Not yet recruiting --> Recruiting | Trial completion date: May 2024 --> May 2025 | Trial primary completion date: May 2024 --> May 2025

Moreover, DNDA elicits a synergistic therapeutic effect when combined with immune checkpoint blockade. The study broadens the application of DNA nanotechnology as an immune stimulator for cGAS-STING activation.

P1, N=34, Completed, Takeda | Active, not recruiting --> Completed | N=65 --> 34

Herein, we design and fabricate a co-axial 3D-printed scaffold integrating a non-nucleotide STING agonist, SR-717, and an AKT inhibitor, MK-2206, in its respective shell and core layers, to synergistically enhance STING activation, thereby suppressing tumor recurrence and growth...Furthermore, the scaffold promotes the recruitment and enrichment of activated dendritic cells and M1 macrophages, subsequently stimulating anti-tumor T cell activity, thereby amplifying the immunotherapeutic effect. This precise and synergistic activation of STING by the scaffold offers promising potential in tumor immunotherapy.

As an immune enhancer, they are used in the treatment of tumors, which has received extensive attention from scientific community and pharmaceutical companies. Despite the multiple challenges that have appeared, STING agonists may offer opportunities for immunotherapy.

In contrast, in breast carcinoma tumors each therapy caused the drop in the number of infiltrating CD8+ T cells.The obtained results indicate an additional therapeutic benefit from combining STING agonist with an anti-vascular agent. However, this effect depends on the type of tumor, the status of its microenvironment and the expression of specific proteins such as STING and αvβ3 family integrin.

Furthermore, this approach led to improved survival and tumor regression without causing any systemic toxicity in melanoma and lung metastasis models. These findings suggest that mRNA encoding IL-12 in conjunction with STING agonists has the potential to confer superior clinical outcomes, representing a promising advancement in cancer immunotherapy.

In this system, Epirubicin (EPI) as an immunogenic cell death (ICD) inducer was coupled to a branched glycopolymer via hydrazone bonds and diABZI as a stimulator of interferon genes (STING) agonist was encapsulated into mB4S...Treatment with mB4S in combination with an anti-PD-L1 antibody elicited potent immune responses by increasing the ratio of matured dendritic cells (DCs) and CD8+ T cells, promoting cytokines secretion, up-regulating M1-like tumor-associated macrophages (TAMs) and down-regulating immunosuppressive myeloid-derived suppressor cells (MDSCs). Therefore, this nanosystem for co-delivery of an ICD inducer and a STING agonist achieved promotion of DCs maturation and CD8+ T cells infiltration, creating an immuno-supportive microenvironment, thus potentiating the therapy effect of the anti-PD-L1 antibody in both 4T1 breast and CT26 colon tumor mice.

In 2020, a non-nucleotide STING agonist MSA-2 was identified, which exhibited satisfactory antitumor effects in animal studies and is amenable to oral administration. Due to its distinctive binding mode and enhanced bioavailability, there have been accumulating interests and an array of studies on MSA-2 and its derivatives, spanning its structure-activity relationship, delivery systems, applications in combination therapies, etc. Here, we provide a comprehensive review of MSA-2 and interventional strategies based on this family of STING agonists to help more researchers extend the investigation on MSA-2 in the future.

An alternative phosphorothioate (referred to as endo-S-phosphorothioate) whereby the sulfur atom is endo to the cyclic phosphate ring (i.e. 5'-S-phosphorothioester linkage) would not have chirality at phosphorus and hence not pose diastereomer separation problems. Herein, we report the design and synthesis of novel 5'-endo-phosphorothioate substituted 2'3'cGAMP analogues that are hydrolytically stable towards both ectonucleotide phosphodiesterase I (ENPP1, a mammalian phosphodiesterase) and poxvirus immune nucleases (poxin, a phosphodiesterase in Poxvirus) but retains STING-TBK1-IRF activation, comparable to clinical candidate, ADU-S100 in THP1 monocytes.

P1, N=98, Active, not recruiting, GlaxoSmithKline | Trial completion date: Apr 2024 --> Mar 2025 | Trial primary completion date: Apr 2024 --> Mar 2025

P1, N=54, Completed, Bristol-Myers Squibb | Active, not recruiting --> Completed | N=190 --> 54

Consistent with this, the use of IL-18 receptor negative CART impair anti-tumor responses in mice receiving combination treatment. In summary, we find that IMSA101 enhances CART function which is facilitated through STING agonist-induced IL-18 secretion.