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

Nano Research 2022年第7期15卷 6328-6339页

作者： Bo-Dou Zhang Jun-Jun Wu Wen-Hao Li Hong-Guo Hu Lang Zhao Pei-Yang He Yu-Fen Zhao Yan-Mei Li Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology(Ministry of Education) Department of ChemistryCenter for Synthetic and Systems BiologyTsinghua UniversityBeijing 100084China Beijing Institute for Brain Disorders Beijing 100069China Institute of Drug Discovery Technology Ningbo UniversityNingbo 315201China

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 Tcell 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.

关键词： nanovaccines stimulator of interferon gene(STING) toll-like receptor 7/8 synergistic immune activation lymph node targeting

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