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

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

  • Mol Ther. 2025 Sep 22:S1525-0016(25)00761-0. doi: 10.1016/j.ymthe.2025.09.032.
Hongxia Zhang 1,  Yang Lin 2,  Liying Wang 3,  Lei Cui 4,  Zining Wang 4,  Xinru You 5,  Chunyuan Xie 4,  Huanling Zhang 4,  Yongxiang Liu 4,  Mengyun Li 6,  Xiaojuan Wang 4,  Jun Wu 7,  Xiaojun Xia 8
Affiliations

Affiliations

  • 1 Department of Pathology, Nanfang Hospital, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou 510515, China. Electronic address: zhanghx23@smu.edu.cn.
  • 2 Department of Pathology, Nanfang Hospital, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 3 Department of Anesthesiology, General Hospital of Southern Theatre Command of PLA, Guangzhou 510010, China.
  • 4 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
  • 5 Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 6 MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
  • 7 Bioscience and Biomedical Engineering Thrust, The Hong Kong University of Science and Technology (Guangzhou), Nansha, Guangzhou 511458, China. Electronic address: junwuhkust@ust.hk.
  • 8 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Hainan Academy of Medical Sciences, Hainan Medical University, Haikou 571199, China. Electronic address: xiaxj@sysucc.org.cn.
PMID: 40988339 DOI: 10.1016/j.ymthe.2025.09.032
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 improves mRNA delivery and antigen presentation through TLR4 signaling activation. Although the 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 the mRNA vaccine, we screened several innate immune receptor agonists and identified the STING agonist as an effective Adjuvant for C1-mRNA vaccine, which could effectively promote the production of type I interferon and pro-inflammatory cytokines including IL-12 and TNF-α in dendritic cells. Such a 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.

Keywords

C1-mRNA cancer vaccine; STING agonist; TNF-α; cancer immunotherapy; innate immunity.

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