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A protein-based cGAS-STING nanoagonist enhances T cell-mediated anti-tumor immune responses
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A protein-based cGAS-STING nanoagonist enhances T cell-mediated anti-tumor immune responses
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A protein-based cGAS-STING nanoagonist enhances T cell-mediated anti-tumor immune responses
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Journal Article
A protein-based cGAS-STING nanoagonist enhances T cell-mediated anti-tumor immune responses
2022
نظرة عامة
cGAS-STING pathway is a key DNA-sensing machinery and emerges as a promising target to overcome the immunoresistance of solid tumors. Here we describe a bovine serum albumin (BSA)/ferritin-based nanoagonist incorporating manganese (II) ions and β-lapachone, which cooperatively activates cGAS-STING signaling in dendritic cells (DCs) to elicit robust adaptive antitumor immunity. Mn
2+
-anchored mannose-modified BSAs and β-lapachone-loaded ferritins are crosslinked to afford bioresponsive protein nanoassemblies, which dissociate into monodispersive protein units in acidic perivascular tumor microenvironment (TME), thus enabling enhanced tumor penetration and spatiotemporally controlled Mn
2+
and β-lapachone delivery to DCs and tumor cells, respectively. β-lapachone causes immunogenic tumor cell apoptosis and releases abundant dsDNA into TME, while Mn
2+
enhances the sensitivity of cGAS to dsDNA and augments STING signaling to trigger downstream immunostimulatory signals. The cGAS-STING nanoagonist enhances the tumor-specific T cell-mediated immune response against poorly immunogenic solid tumors in vivo, offering a robust approach for immunotherapy in the clinics.
Manganese has a crucial role in cGAS-STING-mediated DNA sensing and has emerged as a STING agonist. Here the authors report the design and characterization of a nanosystem incorporating manganese ions and the chemotherapeutic drug β-lapachone, inducing T-cell mediated anti-tumor immune responses in preclinical cancer models.
