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

Xuan Wang, Yingqi Liu, Chencheng Xue, Yan Hu, Yuanyuan Zhao, Kaiyong Cai, Menghuan Li () and Zhong Luo ()
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Xuan Wang: Chongqing University
Yingqi Liu: Chongqing University
Chencheng Xue: Chongqing University
Yan Hu: Chongqing University
Yuanyuan Zhao: Chongqing University
Kaiyong Cai: Chongqing University
Menghuan Li: Chongqing University
Zhong Luo: Chongqing University

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: Abstract 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. Mn2+-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 Mn2+ and β-lapachone delivery to DCs and tumor cells, respectively. β-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.

Date: 2022
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DOI: 10.1038/s41467-022-33301-0

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