A STING agonist potentiates C1 lipidoid-based mRNA cancer vaccine through promoting TNF-α secretion in vivo.

IF 12 1区医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Molecular Therapy Pub Date : 2025-09-22 DOI:10.1016/j.ymthe.2025.09.032

Hongxia Zhang,Yang Lin,Liying Wang,Lei Cui,Zining Wang,Xinru You,Chunyuan Xie,Huanling Zhang,Yongxiang Liu,Mengyun Li,Xiaojuan Wang,Jun Wu,Xiaojun Xia

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引用次数: 0

Abstract

Intracellular delivery of antigen-encoding mRNA-based vaccine has shown great potential in the treatment of cancer and infectious diseases. We previously developed a minimalist cancer nanovaccine using C1 lipidoid nanoparticle with self-adjuvant activity, which markedly improve mRNA delivery and antigen presentation through TLR4 signaling activation. Although C1-mRNA nanovaccine induced strong antitumor efficiency in prophylactic and therapeutic settings, it could not eliminate tumors with low immunogenicity. To further improve the therapeutic efficacy of mRNA vaccine, we screened several innate immune receptor agonists and identified STING agonist as an effective adjuvant for C1-mRNA vaccine, which could effectively promote the production of type I interferon and proinflammatory cytokines including IL-12 and TNF-α in dendritic cells. Such C1-mRNA cancer vaccine adjuvanted with STING agonist effectively promoted antigen presentation in dendritic cells and enhanced T cell activation and exhibited strong antitumor activity on tumor models. Mechanistically, this mRNA vaccine showed improved antitumor efficacy largely depending on STING protein expression in dendritic cells and TNF-α induction in vivo, while type I interferon or IL-12 induction seemed dispensable. Together, by optimizing the antitumor efficacy of C1-mRNA cancer vaccine with STING agonist, this work provides a potential mRNA cancer vaccine platform for treating a wide range of tumor types.

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STING激动剂通过促进体内TNF-α分泌来增强基于C1类脂质mRNA的癌症疫苗。

抗原编码mrna疫苗的细胞内递送在癌症和传染病的治疗中显示出巨大的潜力。我们之前开发了一种极简癌症纳米疫苗，使用具有自佐剂活性的C1类脂质纳米颗粒，通过TLR4信号激活显着改善mRNA传递和抗原呈递。尽管C1-mRNA纳米疫苗在预防和治疗方面具有较强的抗肿瘤效果，但它不能消除低免疫原性的肿瘤。为了进一步提高mRNA疫苗的治疗效果，我们筛选了几种天然免疫受体激动剂，并鉴定了STING激动剂作为C1-mRNA疫苗的有效佐剂，可以有效促进树突状细胞中I型干扰素和IL-12、TNF-α等促炎细胞因子的产生。经STING激动剂佐剂的C1-mRNA肿瘤疫苗可有效促进树突状细胞抗原呈递，增强T细胞活化，在肿瘤模型上表现出较强的抗肿瘤活性。从机制上讲，该mRNA疫苗的抗肿瘤效果在很大程度上取决于树突状细胞中STING蛋白的表达和体内TNF-α的诱导，而I型干扰素或IL-12的诱导似乎是必不可少的。总之，通过优化含有STING激动剂的C1-mRNA癌症疫苗的抗肿瘤效果，本工作为治疗多种肿瘤类型提供了一个潜在的mRNA癌症疫苗平台。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Therapy 医学-生物工程与应用微生物

CiteScore

19.20

自引率

3.20%

发文量

357

审稿时长

3 months

期刊介绍： Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.