A protein-based cGAS-STING nanoagonist enhances T cell-mediated anti-tumor immune responses

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 beta-lapachone, which cooperatively activates cGAS-STING signaling in dendritic cells (DCs) to elicit robust adaptive antitumor immunity. Mn2+-anchored mannose-modified BSAs and beta-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 Mn2+ and beta-lapachone delivery to DCs and tumor cells, respectively. beta-lapachone causes immunogenic tumor cell apoptosis and releases abundant dsDNA into TME, while Mn2+ 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 beta-lapachone, inducing T-cell mediated anti-tumor immune responses in preclinical cancer models.