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.

Interestingly, some of our synthesized LNA 3'3'-endo-S-CDNs can moderately activate hSTING REF haplotype (R232H), which exhibit diminished response to both 2'3'-cGAMP and ADU-S100. Also, we show that one of our most potent endo-S-CDNs has remarkable chemical (oxidants I2 and H2O2) and phosphodiesterase stability.

P1, N=32, Terminated, Synlogic | N=70 --> 32 | Recruiting --> Terminated; Business reasons

Our findings revealed that diABZI enhanced the immunotherapy efficacy of TCR-T by activating STING media and TCR signaling pathways, improving interferon-γ expression, and increasing antigens presentation of tumor cells. This indicates that STING agonist could be used as a strategy to promote TCR-T cancer immunotherapy.

P1/2, N=162, Recruiting, Tyligand Bioscience (Shanghai) Limited | Not yet recruiting --> Recruiting

The production of IFN-β was elevated in all treated groups. The current study suggests that a combination therapy using IFN-gamma, STING agonist, and anti-PD-1 antibody can provide a promising approach to the treatment of GC.

Moreover, MSA-2 triggered the trafficking and infiltration of CD8+ T cells, supported by the generation of a chemokine milieu that promoted recruitment and modulation of the immunosuppressive TME in ccRCC. These findings suggest that MSA-2 potentially serves an effective and preferable adjuvant immunotherapy of ccRCC.

P1, N=39, Completed, Boehringer Ingelheim | Active, not recruiting --> Completed

Combining MSA-2 with immune checkpoint inhibitors presents a transformative approach, holding promise for improved prognosis. Further investigations are warranted to explore the broader immune landscape and potential long-term effects of MSA-2 in cervical cancer treatment.

Thus, we demonstrate that polySTING delivers STING agonists to professional APCs after systemic administration, generating efficacious DC-driven antitumor immunity with minimal side effects. This new polymeric prodrug platform may offer new opportunities for combining efficient targeted STING agonist delivery with other selective tumor therapeutic strategies.

As far as could be ascertained, this is the first report of the in vivo induction, identification, and confirmation of a phenotype of the memory-like NK cells through a prophylactic effect via the use of an immunotherapeutic drug. Our findings provide novel insights into the in vivo induction of CD11bhighCD27low memory-like NK cells thus paving the way for the development of efficient immunotherapies.

P1, N=35, Not yet recruiting, Actym Therapeutics, Inc.

These results show that VPS34 inhibition augments the cGAS/STING pathway, leading to greater tumor control through immune-mediated mechanisms. We propose that pharmacological VPS34 inhibition may synergize with emerging therapies targeting the cGAS/STING pathway.

Furthermore, uniSTING displays an effective antitumour response superior to 2'3'-cGAMP and ADU-S100...Extracellular vesicles released from uniSTING-treated tumour cells further sensitize dendritic cells via exosome-containing miRNAs that reduced the immunosuppressive Wnt2b, and a combination of LNP-uniSTING-mRNA with α-Wnt2b antibodies synergistically inhibits tumour growth and prolongs animal survival. Collectively, these results demonstrate the LNP-mediated delivery of uniSTING-mRNA as a strategy to overcome the current STING therapeutic barriers, particularly for the treatment of multiple cancer types in which STING is downregulated or absent.

However, their clinical development has been challenging due to the poor pharmacokinetic and physicochemical properties. This review discusses drug delivery efforts to circumvent the challenges, their accomplishment, and unmet needs based on the last five years of literature.

P1, N=24, Terminated, Eisai Inc. | Completed --> Terminated; The study was terminated earlier due to a business decision; which was unrelated to safety. In addition, there was no clinical activity data that informed the decision.

P1, N=57, Recruiting, HitGen Inc. | Trial completion date: Jun 2024 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Jun 2024

This strategy also promoted the depletion of immunosuppressive cells, potentially alleviating the immunosuppressive TME. In conclusion, our study highlights the combination of DOX-induced ICD and the immune-enhancing properties of cGAMP holds significant implications for future research and clinical applications.

P1, N=162, Recruiting, Mersana Therapeutics | Suspended --> Recruiting | Trial completion date: Nov 2025 --> Apr 2027 | Trial primary completion date: Nov 2025 --> Apr 2027

P1, N=146, Recruiting, invoX Pharma Limited | Phase classification: P1a/1b --> P1 | Trial completion date: Oct 2025 --> Mar 2027 | Trial primary completion date: Oct 2023 --> Mar 2027

We hypothesized that combined treatment of melanoma-bearing mice with STING agonist ADU-S100 together with antagonists of regulatory ISGs would result in improved control of tumor growth vs. treatment with ADU-S100 alone...Immune changes in the TME associated with improved treatment outcomes were subtle but included increases in proinflammatory innate immune cells and activated CD8+CD69+ T cells and varied between the two tumor models. These data suggest contextual differences in the relative contributions of individual regulatory ISGs that serve to operationally limit the anti-tumor efficacy of STING agonists which should be considered in future design of novel combination protocols for optimal treatment benefit.

An analysis of the tumor microenvironment demonstrated that conjugate I could enhance the infiltration of natural killer (NK) cells into tumors and promote the activation of T cells, NK cells and dendritic cells in tumor tissues. These findings indicated that conjugate I, which was created by incorporating a Pt chemotherapeutic drug and STING agonist into one molecule, is a promising and potent anticancer drug candidate, opening new avenues for small-molecule-based cancer metalloimmunotherapy.

P1, N=18, Active, not recruiting, GlaxoSmithKline | Recruiting --> Active, not recruiting | N=72 --> 18 | Trial completion date: Dec 2025 --> Mar 2024 | Trial primary completion date: Dec 2025 --> Mar 2024

The main effector cells would be NK cells, and the activation of NK cells by the STING-LNPs may avoid the increased expression of immune checkpoint molecules. These findings provide useful insights into the development of an effective immunotherapy against metastatic RCC.

Moreover, IFN-α and CXCL10 production by in vitro stimulated (i.e. with R848, CpG-A, ADU-S100) pDCs exposed to melanoma cell lines supernatants (SN-mel) was tested by intracellular flow cytometry and ELISA...Melanoma-derived immunosuppressive cytokines and a metabolic drift represent relevant mechanisms enforcing pDC-mediated melanoma escape. These findings propose a new window of intervention for novel immunotherapy approaches to amplify the antitumor innate immune response in cutaneous melanoma (CM).

In the colon carcinoma MC38 model (sensitive to immune checkpoint immunotherapy tumor) and melanoma B16F10 model (poorly immunogenic and highly aggressive tumor), the MSA-2-Pt had a good antitumor effect, which was a little better than MSA-2 with intratumor injections. The results present a promising strategy for STING activation in tumor immunotherapy and broadening platinum-based drugs.

As a result, PDIC-NS had realized remarkable in vivo antitumor activity, and backward verified on STING knock out mice. Overall, this study states that PDIC-NS can function as three-in-one small-molecule STING agonist characterized by promoting the content and biostability of endogenous CDNs as well as possessing good tissue specificity, and hence presents an innovative strategy and platform for tumor chemo-immunotherapy.

P1, N=27, Terminated, Stingthera, Inc. | Trial completion date: Jul 2026 --> Jan 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Feb 2026 --> Jan 2024; Sponsor decision (not due to safety concerns)

In THP1-Lucia cells, prodrug 9 also retained a high bioactivity with the EC of 0.96 μM, which was 51-, 43-, and 3-fold more than the 2',3'-cGAMP (EC = 48.6 μM), the parent compound 3',3'-c-di-dAMP (EC = 41.3 μM), and ADU-S100 (EC = 2.9 μM)...Furthermore, prodrug 9 could also improve the transcriptional expression levels of IFN-β, CXCL10, IL-6, and TNF-α in THP-1 cells. These results will be helpful to the development of chemically controllable CDN prodrugs with a high cellular permeability and potency.

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

P1, N=190, Active, not recruiting, Bristol-Myers Squibb | Trial completion date: Nov 2025 --> Apr 2024 | Trial primary completion date: Aug 2025 --> Apr 2024

Notably, significant antitumor effects were achieved with both intratumoral and intraperitoneal administration of M335. These findings suggest the potential of M335 as a promising agent for cancer immunotherapy, which will promote the development of STING agonists in anti-tumor applications.

Moreover, we demonstrated that our K3/c-di-AMP vaccine formulation with 20-mer OVA peptide was capable of controlling tumor growth and improving survival in B16-F10-OVA tumor-bearing C57BL/6 mice and synergized with anti-PD-1 treatment. Together, our findings demonstrate that the K3/c-di-AMP vaccine formulation induces potent T cell immunity against synthetic long peptides and is a promising candidate to improve neoantigen vaccine platform.

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

Furthermore, the challenges and opportunities in developing next-generation STING agonist delivery systems are elaborated. This review aims to serve as a reference for researchers in designing novel and effective STING agonist delivery systems for cancer immunotherapy.

Combinations of ALG-031048 and ICIs further enhanced the in vivo anti-tumor activity. This initial demonstration of anti-tumor activity after systemic administration of ALG-031048 warrants further investigation, while the combination of systemically administered ALG-031048 with ICIs offers an attractive approach to overcome key limitations of ICIs in the clinic.

P1/2, N=313, Recruiting, Takeda | Phase classification: P1a/1b --> P1/2 | N=118 --> 313 | Trial completion date: Mar 2025 --> Aug 2026 | Trial primary completion date: Mar 2025 --> Aug 2026

Of particular interest, 2'3'-c-di-AM(PS)(Rp,Rp) reduces IL-17A production and IL23R expression by human T17 cells while it favors the generation of regulatory T (T) cells. These findings suggest that STING agonists may be promising approaches for treating human T17-mediated chronic inflammation.

The combination of venetoclax and STING agonist shows marked efficacy in ex vivo and in vivo studies, including in models of TP53 defective AML. Combining STING agonists with venetoclax represents a highly promising and novel therapeutic approach for AML and should be considered for accelerated early phase clinical trials.

In this study, we investigated the immunotherapeutic effects of ADU-S100 as a STING agonist and CpG ODN1826 as a TLR9 agonist in a preclinical model of colon carcinoma. Remarkably, the significant downregulation of CAFs in the TME indicated that suppression of tumorigenesis occurred after immunoadjuvant therapy. The results illustrate the potential of targeting the STING and TLR9 pathways as powerful immunoadjuvants in the treatment of preclinical colon carcinoma and the possibility of harnessing these pathways in future therapeutic approaches.