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. 2022 Apr 18;15(7):6328–6339. doi: 10.1007/s12274-022-4282-x

STING and TLR7/8 agonists-based nanovaccines for synergistic antitumor immune activation

Bo-Dou Zhang 1, Jun-Jun Wu 1, Wen-Hao Li 1, Hong-Guo Hu 1, Lang Zhao 1, Pei-Yang He 1, Yu-Fen Zhao 1,3, Yan-Mei Li 1,2,✉
PMCID: PMC9014842  PMID: 35464625

Abstract

Immunostimulatory therapies based on pattern recognition receptors (PRRs) have emerged as an effective approach in the fight against cancer, with the ability to recruit tumor-specific lymphocytes in a low-immunogenicity tumor environment. The agonist cyclic dinucleotides (CDNs) of the stimulator of interferon gene (STING) are a group of very promising anticancer molecules that increase tumor immunogenicity by activating innate immunity. However, the tumor immune efficacy of CDNs is limited by several factors, including relatively narrow cytokine production, inefficient delivery to STING, and rapid clearance. In addition, a single adjuvant molecule is unable to elicit a broad cytokine response and thus cannot further amplify the anticancer effect. To address this problem, two or more agonist molecules are often used together to synergistically enhance immune efficacy. In this work, we found that a combination of the STING agonist CDGSF and the Toll-like receptor 7/8 (TLR7/8) agonist 522 produced a broader cytokine response. Subsequently, we developed multicomponent nanovaccines (MCNVs) consisting of a PC7A polymer as a nanocarrier encapsulating the antigen OVA and adjuvant molecules. These MCNVs activate bone marrow-derived dendritic cells (BMDCs) to produce multiple proinflammatory factors that promote antigen cross-presentation to stimulate specific antitumor T-cell responses. In in vivo experiments, we observed that MCNVs triggered a strong T-cell response in tumor-infiltrating lymphocytes, resulting in significant tumor regression and, notably, a 100% survival rate in mice through 25 days without other partnering therapies. These data suggest that our nanovaccines have great potential to advance cancer immunotherapy with increased durability and potency.

graphic file with name 12274_2022_4282_Fig1_HTML.jpg

Electronic Supplementary Material

Supplementary material (synthesis of CDGSF, 522, PC7A and OVA; preparation of MCNVs; representative gating strategies for flow cytometry) is available in the online version of this article at 10.1007/s12274-022-4282-x.

Keywords: nanovaccines, stimulator of interferon gene (STING), Toll-like receptor 7/8, synergistic immune activation, lymph node targeting

Electronic Supplementary Material

12274_2022_4282_MOESM1_ESM.pdf (1MB, pdf)

STING and TLR7/8 agonists-based nanovaccines for synergistic antitumor immune activation

Acknowledgements

This work was supported by the National Key R&D Program of China (Nos. 2019YFA0904200 and 2018YFA0507600), Tsinghua University Spring Breeze Fund (No. 2020Z99CFY042), and the National Natural Science Foundation of China (No. 92053108).

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STING and TLR7/8 agonists-based nanovaccines for synergistic antitumor immune activation

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