{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["10(3)"],"submitter":["Nguyen DC"],"pubmed_abstract":["The Stimulator of Interferon Genes (STING) pathway is a promising target for cancer immunotherapy. Despite recent advances, therapies targeting the STING pathway are often limited by routes of administration, suboptimal STING activation, or off-target toxicity. Here, we report a dendritic cell (DC)-targeted polymeric prodrug platform (polySTING) that is designed to optimize intracellular delivery of a diamidobenzimidazole (diABZI) small-molecule STING agonist while minimizing off-target toxicity after parenteral administration. PolySTING incorporates mannose targeting ligands as a comonomer, which facilitates its uptake in CD206<sup>+</sup>/mannose receptor<sup>+</sup> professional antigen-presenting cells (APCs) in the tumor microenvironment (TME). The STING agonist is conjugated through a cathepsin B-cleavable valine-alanine (VA) linker for selective intracellular drug release after receptor-mediated endocytosis. When administered intravenously in tumor-bearing mice, polySTING selectively targeted CD206<sup>+</sup>/mannose receptor<sup>+</sup> APCs in the TME, resulting in increased cross-presenting CD8<sup>+</sup> DCs, infiltrating CD8<sup>+</sup> T cells in the TME as well as maturation across multiple DC subtypes in the tumor-draining lymph node (TDLN). Systemic administration of polySTING slowed tumor growth in a B16-F10 murine melanoma model as well as a 4T1 murine breast cancer model with an acceptable safety profile. 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."],"journal":["ACS central science"],"pagination":["666-675"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10979423"],"repository":["biostudies-literature"],"pubmed_title":["Mannosylated STING Agonist Drugamers for Dendritic Cell-Mediated Cancer Immunotherapy."],"pmcid":["PMC10979423"],"pubmed_authors":["Sellers DL","Nguyen DC","Song K","Jokonya S","Zakaria A","Yazdani O","Pun SH","Wang Y","Stayton PS"],"additional_accession":[]},"is_claimable":false,"name":"Mannosylated STING Agonist Drugamers for Dendritic Cell-Mediated Cancer Immunotherapy.","description":"The Stimulator of Interferon Genes (STING) pathway is a promising target for cancer immunotherapy. Despite recent advances, therapies targeting the STING pathway are often limited by routes of administration, suboptimal STING activation, or off-target toxicity. Here, we report a dendritic cell (DC)-targeted polymeric prodrug platform (polySTING) that is designed to optimize intracellular delivery of a diamidobenzimidazole (diABZI) small-molecule STING agonist while minimizing off-target toxicity after parenteral administration. PolySTING incorporates mannose targeting ligands as a comonomer, which facilitates its uptake in CD206<sup>+</sup>/mannose receptor<sup>+</sup> professional antigen-presenting cells (APCs) in the tumor microenvironment (TME). The STING agonist is conjugated through a cathepsin B-cleavable valine-alanine (VA) linker for selective intracellular drug release after receptor-mediated endocytosis. When administered intravenously in tumor-bearing mice, polySTING selectively targeted CD206<sup>+</sup>/mannose receptor<sup>+</sup> APCs in the TME, resulting in increased cross-presenting CD8<sup>+</sup> DCs, infiltrating CD8<sup>+</sup> T cells in the TME as well as maturation across multiple DC subtypes in the tumor-draining lymph node (TDLN). Systemic administration of polySTING slowed tumor growth in a B16-F10 murine melanoma model as well as a 4T1 murine breast cancer model with an acceptable safety profile. 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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Mar","modification":"2025-04-22T08:24:37.35Z","creation":"2025-04-05T22:31:32.292Z"},"accession":"S-EPMC10979423","cross_references":{"pubmed":["38559305"],"doi":["10.1021/acscentsci.3c01310"]}}