ADU-S100

Using a syngeneic mouse model of genetically engineered Egfr-mutant NSCLC, we evaluated the antitumor effects of STING agonist ADU-S100, alone and combined with osimertinib. Crucially, the combination induced an abscopal effect accompanied by PD-1+/CD8+ cell infiltration. Combining osimertinib with a STING agonist augmented innate and adaptive immunity, inducing systemic antitumor responses in EGFR-mutant NSCLC.

Pharmacological activation using cyclic dinucleotides (CDN) STING agonists (ADU-S100 and MK-1454) and non-CDN STING agonists (diABZI and MSA-2), as well as MPS1 inhibitors (CFI-402257, BAY-1217389, and CC-671), has effectively triggered strong type I interferon responses and caused tumour regression in preclinical and clinical trials. When combined with radiotherapy, PARP inhibitors, or immune checkpoint blockers, these agents exhibit enhanced synergy but are constrained by tumour heterogeneity and context-dependent toxicity. Here, we reviewed the complexity of the cGAS-STING and its potential as a double-edged sword in cancer treatment, underscoring the need for strict strategies to harness this pathway while enhancing antitumour immunity and mitigating pro-tumorigenic effects.

In contrast, early-phase clinical trials of STING agonists, including ADU-S100, SYNB1891, IMSA101, and MK-1454, have shown acceptable safety and pathway engagement but generally modest and variable clinical responses, primarily reflected by low objective response rates and limited disease stabilization. We highlight emerging drug delivery platforms, such as nanocarriers, antibody-drug conjugates, and exosome-based systems, as key modulators of efficacy and safety, and emphasize the importance of biomarker-guided approaches for patient stratification and trial optimization. By integrating biological insight with translational feasibility, this review provides a framework for advancing STING-based combination immunotherapy toward more durable and personalized cancer treatment.

To address these limitations, we have engineered cationic quaternary ammonium salt-based drug-eluting microspheres capable of loading 131I and ADU-S100...This approach effectively overcomes the current limitations of poor embolic efficacy and non-target embolization associated with radioactive microspheres. Moreover, it activates the tumor immune microenvironment, addressing the issue of tumor immune resistance and further improving therapeutic outcomes, thereby showing great clinical application potential.

Activation of STING pathway by ADU-S100 enhances the antitumor efficacy of doxorubicin in STS. Combining doxorubicin with STING agonists may be a promising therapeutic strategy worth exploring in future clinical trials.

Candidates such as ADU-S100 and MSA-2 demonstrate enhanced STING activation and clinical potential...Future directions emphasize the development of smart nanocarriers with spatiotemporal control, biomarker-driven patient stratification, and combinatorial regimens that integrate epigenetic or metabolic modulators. This review underscores the transformative potential of cGAS-STING-targeted therapies while outlining critical hurdles and interdisciplinary strategies to advance precision cancer immunotherapy.

NanoSTING@Mn, composed of ADU-S100 complexed with Mn2⁺ and encapsulated in biomimetic liposomes, potently activates the cGAS-STING pathway, induces a type I interferon response, and promotes lymphocyte infiltration...Upon intravenous rechallenge, disseminated tumor cells are eliminated, preventing metastasis and ensuring long-term protection. This synergistic approach offers a scalable platform to boost immunotherapy efficacy and redefines immune-based metastasis prevention strategies.

In this work, a therapeutic gel scaffold made from Mn2+-cross-linked sodium alginate (Mn(II)-SA-Gel), which contains a stimulator of interferon genes (STING) agonist (ADU-S100) and an immune checkpoint inhibitor (aCTLA-4), was developed as a drug delivery system for cancer therapy...Moreover, Mn2+ promotes the generation of highly cytotoxic hydroxyl free radicals in the presence of H2O2, and in combination with the immune checkpoint inhibitor aCTLA-4, enhances the T-cell immune response to enhance their powerful tumor cell-killing effect. The findings indicated that Mn(II)-SA-Gel could serve as a promising platform to synergistically stimulate the STING pathway, thereby improving cancer immunotherapy.

Incorporating lymphocyte activation gene 3 (LAG3) blockade further strengthens systemic antitumor immunity by suppressing myeloid-derived suppressor cells while augmenting type 2 conventional dendritic cells, cytotoxic T lymphocytes, and tissue-resident memory T cells. Our findings highlight the potential of STBF-PDT-STING agonism-anti-LAG3 combinations for metastatic and locally advanced cSCC.

LASIP is a transformative dissolvable microneedle patch loaded with antiPD-L1 antibodies, liposomal formulation of drugs (ADU-S100) that activate the stimulator of interferon genes (STING) pathway, and liposomal formulation of a biocompatible dye (IR783) that converts near-infrared light to mild hyperthermia (∼43 °C)...We show an "immunometabolic" correlation of these key metabolites to markers of DC maturation, Tregs, STING activation, and cytokines. Our findings demonstrate that by integrating three treatment modalities, LASIP elicits both innate and adaptive immune responses and enables metabolic reprogramming in the tumor microenvironment to enable antitumor immunity.

Current therapeutic strategies prioritize isoform-specific agonists (e.g. cyclic dinucleotides like ADU-S100; non-CDNs like diABZI) and precision delivery systems, such as nanoparticles and engineered bacteria, to address challenges like short half-life and systemic toxicity...However, the pathway's dual roles, particularly its tumor-promoting effects in advanced malignancies, necessitate context-dependent modulation. This review integrates preclinical insights and clinical trial data to outline strategies for harnessing cGAS-STING signaling in cancer immunotherapy while balancing its immunostimulatory and immunosuppressive outputs.

In vivo, treatment with the VPS34 inhibitor SB02024 enhances the positive effects of the STING agonist ADU-S100 in melanoma tumor-bearing mice. Thus, our study suggests that VPS34 inhibitors could be used to enhance STING-based anticancer therapies. CCL5 (C-C motif chemokine 5); CXCL10 (C-X-C motif chemokine 10); IFN (interferon); VPS34 (vacuolar protein sorting 34); cGAS (cyclic GMP-AMP Synthase); STING (stimulator of interferon genes protein); cGAMP (2'3'-cyclic guanosine monophosphate-adenosine monophosphate).