Together, these preclinical data support the potential utility of VB-85247 for treating BCG-unresponsive NMIBC patients and for enhancing the clinical benefit of potential of anti-PD1 in bladder cancer. Based on these data, VB-85247 is being advanced into clinical development.

The responses required RAG2 but not interferons, and cured mice developed immunity to cancer rechallenge requiring CD8+ T cells. These studies provide a framework for enhancing microbial and small molecule innate agonists for cancer, via co-activating STING and TLRs.

P2, N=16, Terminated, ImmuneSensor Therapeutics Inc. | N=51 --> 16 | Trial completion date: Feb 2026 --> Nov 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Nov 2025 --> Nov 2024; Change in ImmuneSensor corporate strategy

P1, N=30, Recruiting, Sichuan Kelun Pharmaceutical Research Institute Co., Ltd. | Trial completion date: Aug 2024 --> Jun 2025 | Trial primary completion date: Aug 2024 --> Jun 2025

Decoy10 and a closely related product, Decoy20, produced single agent anti-tumor activity or combination-mediated durable regression of established subcutaneous, metastatic or orthotopic colorectal, hepatocellular (HCC), pancreatic, and non-Hodgkin's lymphoma (NHL) tumors in mice, with induction of both innate and adaptive immunological memory (syngeneic and human tumor xenograft models). Decoy bacteria combination-mediated regressions were observed with a low-dose, oral non-steroidal anti-inflammatory drug (NSAID), anti-PD-1 checkpoint therapy, low-dose cyclophosphamide (LDC), and/or a targeted antibody (rituximab). Efficient tumor eradication was associated with plasma expression of 15-23 cytokines and chemokines, broad induction of cytokine, chemokine, innate and adaptive immune pathway genes in tumors, cold to hot tumor inflammation signature transition, and required NK, CD4+ and CD8+ T cells, collectively demonstrating a role for both innate and adaptive immune activation in the anti-tumor immune response.

P1, N=2, Active, not recruiting, ImmuneSensor Therapeutics Inc. | Phase classification: P1/2 --> P1 | Trial completion date: Sep 2024 --> Sep 2025 | Trial primary completion date: Sep 2024 --> Sep 2025

Furthermore, we demonstrate the better anti-tumor effect of nanomotor containing the STING agonist than those of the gold standard Bacille Calmette-Guerin therapy and the anti-PD-1 inhibitor pembrolizumab in bladder cancer model. Taken together, the urease-powered nanomotor would provide a paradigm as a next-generation platform for bladder cancer immunotherapy.

The iRGD-STING-PFP@liposomes targeted drug delivery system effectively targets breast cancer cells, providing a new strategy for breast cancer immunotherapy. These findings indicate that iRGD-STING-PFP@liposomes could successfully deliver STING agonists to tumor tissue, trigger the innate immune response, and may serve as a potential platform for targeted immunotherapy.

We found that this thioester-protected compound features a dramatic increase in its cellular potency that rises from EC50 = 5 mM to 25 nM. The new compound is envisioned to enable an efficient STING-agonist-based anticancer therapy.

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.