ADU-S100 / Novartis - LARVOL DELTA

The combination of a STING agonist and IL15 efficiently reverses the immunosuppressive tumor microenvironment in a complex primary human organoid model (ITOC 2025) - "Upon treatment with IL-15, a STING agonist (ADU-S100) or a combination of both for 48 hours immune cell responses and tumor cell death were analyzed by flow cytometry...Tumor cell killing in response to STING pathway stimulation and combination treatment was partially dependent on cell-cell contact as spatial separation of NK cells resulted in a significantly reduced degranulation and tumor cell death. Conclusions Combination treatment of a STING agonist and IL-15 modulates the microenvironment into a pro-inflammatory state and synergistically supports immune cell-mediated tumor cell killing in a TME mimicking 3D model of tumor organoids, CAFs and innate immune cells."

Biomarker • Tumor microenvironment • Colorectal Cancer • Oncology • Solid Tumor • CAFs • IL15 • STING • TNFA

STING agonist ADU-S100 in combination with vemurafenib induces STING upregulation, immune-stimulatory cytokine modulation and enhancing NK-mediated cytotoxicity in BRAF V600E-mutant melanoma (AACR 2025) - "The combination of STING agonist ADU-S100 and vemurafenib effectively enhances immune-stimulatory cytokine profiles in BRAF V600E-mutant melanoma. Notably, this approach may be used to promote NK cell-mediated cytotoxicity and modulation of key cytokines associated with immune resistance. This strategy shows promise for overcoming resistance and improving outcomes, warranting further clinical investigation."

Combination therapy • IO biomarker • Melanoma • Oncology • Solid Tumor • B2M • BRAF • CXCL13 • CXCL5 • CXCL8 • STING

Sting pathway activation potentiates the antitumor efficacy of doxorubicin in soft-tissue sarcoma (AACR 2025) - "STING pathway activation by ADU-S100 enhances the antitumor efficacy of doxorubicin in STS, suggesting that combining doxorubicin with ADU-S100 may be a promising strategy for future clinical trials."

Clinical • IO biomarker • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • PTPRC

INTERFERON STIMULATED GENE SCORES ARE ELEVATED IN THE MYELOID COMPARTMENT OF MURINE KP UNDIFFERENTIATED PLEOMORPHIC TUMORS TREATED WITH TRANSLATIONAL STING AGONISTS (CTOS 2024) - "The objectives of the present study are; 1) To evaluate the anti-tumor potential of two clinically relevant STING agonists; ADU-S100 (CDN) and E7766, 2) To examine the importance of UPS cell STING expression for stimulating anti-tumor responses, and 3) To identify which populations in the UPS TME engage in STING signaling following therapy. To evaluate survival frequencies with translational STING agonists, immune competent C57Bl/6 mice were engrafted with 100,000 UPS cells and treated intratumorally with escalating doses of CDN or E7766 and followed over time using tumor volume measurements and bioluminescence imaging. We are thrilled to report that E7766 is a translational STING agonist capable of stimulating tumor clearance in the KP model of UPS. Additionally, we have established that tumor clearance phenotypes in this model are independent of UPS cell STING expression status. Moreover, neutrophils and myeloid cells in general appear to be important populations in..."

IO biomarker • Preclinical • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Undifferentiated Pleomorphic Sarcoma • STING

Intranasal immunization with CPAF combined with ADU-S100 induces an effector CD4 T cell response and reduces bacterial burden following intravaginal infection with Chlamydia muridarum. (PubMed, Vaccine) - "We determined that intranasal immunization with CPAF plus ADU-S100 was well tolerated in female mice, induced CD4 T cells characterized by TNFα production alone or in combination with IL-17 A or IFNγ, significantly reduced bacterial shedding, and shortened the duration of infection in mice intravaginally challenged with Chlamydia muridarum. These data demonstrate the potential for CDA as a mucosal adjuvant for vaccines against Chlamydia genital tract infection."

Journal • Infectious Disease • Vaginitis • CD4 • IFNG • IL17A • STING • TNFA

Intratumoral STING agonist reverses immune evasion in PD-(L)1-refractory Merkel cell carcinoma: mechanistic insights from detailed biomarker analyses. (PubMed, J Immunother Cancer) - "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."

Biomarker • IO biomarker • Journal • Genetic Disorders • Merkel Cell Carcinoma • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor • CD8 • STING

Intradermal vaccination with a phytoglycogen nanoparticle and STING agonist induces cytotoxic T lymphocyte-mediated antitumor immunity. (PubMed, NPJ Vaccines) - "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."

Journal • Hematological Malignancies • Lymphoma • Melanoma • Oncology • Solid Tumor • CD4 • CD8

Evaluation of Efficacy of Surface Coated versus Encapsulated Influenza Antigens in Mannose-Chitosan Nanoparticle-Based Intranasal Vaccine in Swine. (PubMed, Vaccines (Basel)) - "The vaccine employed whole inactivated H1N2 SwIAV as an antigen and STING-agonist ADU-S100 as an adjuvant, with both surface adsorbed or encapsulated in mannose-chitosan nanoparticles (mChit-NPs)...Importantly, both the mChit-NP vaccines reduced challenge heterologous viral replication in the nasal cavity higher than commercial swine influenza vaccine. In summary, a novel intranasal mChit-NP vaccine platform activated both the arms of the immune system and is a significant advancement in swine influenza vaccine design, demonstrating its potential effectiveness for pig immunization."

Journal • Infectious Disease • Influenza • Respiratory Diseases

Improving STING agonist-based cancer therapy by inhibiting the autophagy-related protein VPS34. (PubMed, Oncoimmunology) - "We have recently demonstrated that inhibiting VPS34 enhances T-cell-recruiting chemokines through the activation of the cGAS/STING pathway using the STING agonist ADU-S100. Combining VPS34 inhibitors with ADU-S100 increased cytokine release and improved tumor control in mouse models, suggesting a potential synergy between VPS34 inhibition and therapies based on STING agonists."

Journal • Genito-urinary Cancer • Melanoma • Oncology • Renal Cell Carcinoma • Solid Tumor

Characterization of a novel functional porcine CD3+CD4lowCD8α+CD8β+ T-helper/memory lymphocyte subset in the respiratory tract lymphoid tissues of swine influenza A virus vaccinated pigs. (PubMed, Vet Immunol Immunopathol) - "To understand the possible functional role/s of these cells, we characterized the antigen-specific T cell memory responses by multi-color flow cytometry in pigs vaccinated with a whole inactivated SwIAV vaccine, formulated with a phytoglycogen nanoparticle/STING agonist (ADU-S100) adjuvant (NanoS100-SwIAV)...These observations highlight the heterogeneity and plasticity of porcine CD4+ T-helper/memory cells in response to respiratory viral infection in pigs. Comprehensive systems immunology studies are needed to further decipher the cellular lineages and functional role/s of this porcine T helper/memory cell subset."

Journal • Preclinical • Infectious Disease • Influenza • Respiratory Diseases • CD4 • IFNG • IL17A

PDE-stable 2'3'-cGAMP analogues, containing 5'-S-phosphorothioester linkage, as STING agonists. (PubMed, RSC Med Chem) - "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."

Journal • Oncology • ENPP1 • GLI2 • STING

2',4'-LNA-Functionalized 5'-S-phosphorothioester CDNs as STING agonist. (PubMed, Chembiochem) - "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."

Journal • Oncology • CGAS • GLI2 • STING

STING agonist ADU-S100 improves the antitumor response of CLDN18.2/CD3 BiTEs by enhancing stem-like tumor-reactive CD8+ T cells in pancreatic adenocarcinoma (AACR 2024) - "By qPCR, western blot and flow cytometry, an orthotopic transplantation mouse model of pancreatic cancer and an in vitro tumor-PBMC coculture system were established to reveal the potential molecular mechanism of STING agonist ADU-S100 in optimizing the effects of CLDN18.2/CD3 BiTEs (IBI389). In PDAC organoids, IBI389 induced potent, specific cytotoxicity, the CLDN18.2 BiTEs significantly engaged human CD3+ T cells with tumor cells in an organoid-PBMC coculture system in vitro, resulting in the formation of the immunological synapse (IS). Pancreatic tumors appear to evade immune response by inducing immune-suppressive tumor microenvironment development. In mice, the combination of STING agonist ADU-S100 and CLDN18.2 BiTEs increased the proportion of memory and stem-like CD4+ and CD8+ T cells while decreasing the proportion of regulatory and exhausted T cells in pancreatic tumors, eradicating all detectable tumors. This data may be utilized to formulate immune-based..."

Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CD8 • CLDN18 • HAVCR2 • IL2RA • IL7R • ISG20 • PD-1

Mannose-chitosan nanoparticle surface adsorbed inactivated influenza virus vaccine elicits cross-protective humoral immunity in pigs (IMMUNOLOGY 2024) - "We developed whole inactivated SwIV H1N2 based mannose-chitosan nanoparticle (mChit-SwIV-NP) vaccine containing STING (stimulator of interferon gene) adjuvant ADU-S100, either both encapsulated (mChit-SwIV+S100-eNP) or surface adsorbed (mChit-SwIV+S100-sNP)...In summary, intranasal mChit-SwIV+S100-sNP vaccine elicited cross-reactive antibody while mChit-SwIV+S100-eNP vaccine induced mucosal and systemic cell-mediated immune responses higher than commercial SwIV vaccinates. Suggesting that mannose-chitosan nanoparticle vaccine has a promise in mitigating SwIV infections and transmission in swine herds."

Infectious Disease • Influenza • Respiratory Diseases • IFNG • IL17A • STING

Role of major facilitative folate transporters SLC19A1 and SLC46A1 in cyclic dinucleotide transport and STING signaling (AACR 2024) - "In R1-11/Tet-on-RFC cells, ADU-S100 showed a low affinity for binding to RFC, as measured by direct competition for transport with [3H]methotrexate...Maximum induction of pIRF3/IFNβ was seen in THP-1 and R1-11/Tet-on-RFC cells by ADU-S100 treatment at pH 7.2 (RFC pH optimum) in the presence of 25 nM leucovorin...In conclusion, RFC mediates ADU-S100 uptake and STING activation under physiologic conditions and this process is enhanced by concomitant expression of PCFT. Additional characterization of key molecular and biochemical determinants of CDN-based cancer therapeutics may lead to improved approaches for CDN therapy based on enhanced cellular uptake."

Oncology • IFNB1 • STING

A complex human tumor organoid model consisting of malignant cells, fibroblasts and immune cells enlights the effect of chemotherapy-induced senescent tumor cells on NK-cell anti-tumor responses (ITOC 2024) - "Senescence was induced by Etoposide treatment and wasverified by β-galactosidase staining. Immune cells were activated by either ionomycinand PMA, or a STING agonist ADU-S100...Moreover, a combination of senescenceinduction by DNA-damaging chemotherapy and subsequent STING-pathway activation ledto a more pronounced NK-cell activation (CD69) and degranulation (CD107a) incontrast to non-senescent controls. Conclusions We developed a complex 3D culturesystem of tumor, stromal and immune cells to mimic the tumor microenvironment andto assess the impact of senescent organoids on STING-activated immune cells in a primary human model."

Immune cell • Tumor cell • Oncology • CAFs • CD69 • LAMP1

Mn-phenolic networks as synergistic carrier for STING agonists in tumor immunotherapy. (PubMed, Mater Today Bio) - "In this study, we present Mn-phenolic networks as a novel carrier for ADU-S100, a hydrophilic STING agonist, aimed at bolstering immunotherapy...This includes the promotion of cytokine release, dendritic cell maturation, and T cell infiltration, leading to pronounced suppression of tumor growth. Combining with the excellent biocompatibility and biodegradability, this Mn-based nanocarrier represents a promising strategy for enhancing tumor immunotherapy through the cGAS-STING pathway."

IO biomarker • Journal • Immunology • Oncology

Universal STING mimic boosts antitumour immunity via preferential activation of tumour control signalling pathways. (PubMed, Nat Nanotechnol) - "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."

Journal • Breast Cancer • Lung Cancer • Melanoma • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8 • STING

Antagonism of regulatory ISGs enhances the anti-melanoma efficacy of STING agonists. (PubMed, Front Immunol) - "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."

IO biomarker • Journal • Melanoma • Oncology • Solid Tumor • ARG2 • CD69 • CD8 • NOS2 • STING

Impaired activation of plasmacytoid dendritic cells via toll-like receptor 7/9 and STING is mediated by melanoma-derived immunosuppressive cytokines and metabolic drift. (PubMed, Front Immunol) - "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)."

IO biomarker • Journal • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • CXCL10 • IFNA1 • STING • TLR7

Dithioethanol (DTE)-Conjugated Deoxyribose Cyclic Dinucleotide Prodrugs (DTE-dCDNs) as STING Agonist. (PubMed, Int J Mol Sci) - "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."

Journal • Oncology • CXCL10 • GLI2 • IFNB1 • IL6 • TNFA

The separation of cyclic diadenosine diphosphorothioate and the diastereomers of its difluorinated derivative and the estimation of the binding constants and ionic mobilities of their complexes with 2-hydroxypropyl-β-cyclodextrin by affinity capillary electrophoresis. (PubMed, Electrophoresis) - "In this work, a new affinity capillary electrophoresis method has been developed and applied for the separation of a potential anticancer drug, 2',3'-cyclic diadenosine diphosphorothioate (R , R ) (ADU-S100), and three recently newly synthesized diastereomers of its difluorinated derivative, 3',3'-cyclic di(2'-fluoro, 2'-deoxyadenosine phosphorothioate)...The formed complexes were found to be relatively weak, with the average apparent binding constants in the range of 12.2-94.1 L mol and with the actual ionic mobilities spanning the interval (-7.8 to -12.7) × 10  m  V  s . The developed method can be applied for the separation, analysis, and characterization of the above and similar CDNs."

Journal • Oncology

Microglial STING activation alleviates nerve injury-induced neuropathic pain in male but not female mice. (PubMed, Brain Behav Immun) - "In contrast, STING activation by specific agonists (ADU-S100, 35 nmol) significantly alleviated neuropathic pain in male mice, but not female mice...Mechanistically, downstream activation of TANK-binding kinase 1 (TBK1) and the production of IFN-ß, may partly account for the analgesic effect observed. These findings suggest that STING activation in spinal microglia could be a potential therapeutic intervention for neuropathic pain, particularly in males."

Journal • Preclinical • Inflammation • Neuralgia • Pain • STING

Characterization of the Efficacy of a Split Swine Influenza A Virus Nasal Vaccine Formulated with a Nanoparticle/STING Agonist Combination Adjuvant in Conventional Pigs. (PubMed, Vaccines (Basel)) - "We investigated the efficacy of split SwIAV H1N2 antigens adsorbed with a plant origin nanoparticle adjuvant [Nano11-SwIAV] or in combination with a STING agonist ADU-S100 [NanoS100-SwIAV]...However, in NanoS100-SwIAV vaccinates, a slight early reduction in the H1N1 pandemic virus and a late reduction in the SwIAV H1N1-OH7 load in the nasal passages were detected. Hence, despite vast genetic differences between the vaccine and both the challenge viruses, IN vaccination with NanoS100-SwIAV induced antigen-specific moderate levels of cross-protective immune responses."

Journal • Infectious Disease • Influenza • Respiratory Diseases • IFNG • IL17A

Intradermal Vaccination against Influenza with a STING-Targeted Nanoparticle Combination Adjuvant Induces Superior Cross-Protective Humoral Immunity in Swine Compared with Intranasal and Intramuscular Immunization. (PubMed, Vaccines (Basel)) - "The monovalent vaccines were adjuvanted with NanoST, a cationic phytoglycogen-based nanoparticle that is combined with the STING agonist ADU-S100...Bone marrow from intradermally and intramuscularly immunized pigs had both IgG and IgA virus-specific antibody-secreting cells. These studies reveal that NanoST is a promising adjuvant system for the intradermal administration of STING-targeted influenza vaccines."

Journal • Infectious Disease • Influenza • Respiratory Diseases • STING