Zhou Shurong, Liang Yuqing, Hao Yu, Wang Qiyan, Xu You, Su Ting, Cheng Furong, Zhu Guizhi
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Pharmaceutics and Center for Pharmaceutical Engineering and Sciences, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
Mol Ther Nucleic Acids. 2025 Jul 1;36(3):102623. doi: 10.1016/j.omtn.2025.102623. eCollection 2025 Sep 9.
Therapeutic vaccines are promising for cancer immunotherapy in combination with immune checkpoint blockade (ICB). Though lipid nanoparticles (LNPs) hold great potential to deliver cancer therapeutic vaccines, LNPs delivering peptide or mRNA vaccines often induce suboptimal T cell responses. Type I interferon (IFN-I) responses can enhance antigen presentation and potentiate T cell responses. Here, we report LNP codelivery of peptide or mRNA vaccines with a cyclic GMP-AMP synthase (cGAS) agonist that can specifically induce IFN-I responses to potentiate anticancer T cell responses for robust ICB combination immunotherapy of tumors. Svg3, an oligonucleotide-based cGAS agonist, can be efficiently coloaded with antigenic peptides or antigen-encoding mRNAs into LNPs and codelivered to mouse draining lymph nodes and antigen-presenting cells (APCs). Svg3 promoted the antigen presentation and antigen-specific CD8 T cell responses in mice. The combination of LNP-delivered Svg3 with peptide or mRNA encoding antigens promotes anti-tumor responses, reduces immune suppression, and enhances tumor therapeutic efficacy when combined with ICB.
治疗性疫苗与免疫检查点阻断（ICB）联合用于癌症免疫治疗具有广阔前景。尽管脂质纳米颗粒（LNP）在递送癌症治疗性疫苗方面具有巨大潜力，但递送肽或mRNA疫苗的LNP通常会诱导次优的T细胞反应。I型干扰素（IFN-I）反应可增强抗原呈递并增强T细胞反应。在此，我们报告了LNP与环状GMP-AMP合酶（cGAS）激动剂共同递送肽或mRNA疫苗，该激动剂可特异性诱导IFN-I反应，以增强抗癌T细胞反应，从而实现对肿瘤的强大ICB联合免疫治疗。基于寡核苷酸的cGAS激动剂Svg3可以与抗原肽或编码抗原的mRNA有效共载入LNP，并共同递送至小鼠引流淋巴结和抗原呈递细胞（APC）。Svg3促进了小鼠体内的抗原呈递和抗原特异性CD8 T细胞反应。当与ICB联合使用时，LNP递送的Svg3与编码抗原的肽或mRNA的组合可促进抗肿瘤反应，减少免疫抑制，并增强肿瘤治疗效果。
