STING agonist-based ER-targeting molecules boost antigen cross-presentation

• 成果类型: Article
• 署名作者: Wang, Xiafeng; Huang, Zhangping; Xing, Lixiao; Shang, Liru; Jiang, Juan; Deng, Caiguanxi; Yu, Wei; Peng, Lin; Yang, Hao; Zheng, Xiaohong; Liu, Xinmin; Yang, Haolan; Chen, Yixin; Li, Yongyong; Liu, Jing; Xie, Xi; Xu, Wei; Xia, Xiaojun; Liu, Zezhong; Liu, Wanli; Jiang, Shibo; Zeng, Yingyue; Lu, Lu; Wang, Ji
• 署名单位: Sun Yat Sen University; Sun Yat Sen University; Fudan University; Fudan University; Liaoning University; Sun Yat Sen University; Sun Yat Sen University; State Key Lab Oncology South China; Fudan University; Fudan University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2653
• DOI: 10.1038/s41586-025-08758-w
• 发表日期: 2025-05-01
• 关键词: cyclic gmp-amp; endoplasmic-reticulum; dendritic cells; neoantigen vaccine; immunity; peptide; protein; induction

摘要

CD8+ T cell immune responses are critical for combating infectious diseases and tumours1, 2-3. Antigen cross-presentation, primarily occurring at the endoplasmic reticulum (ER) of dendritic cells, is essential for protein-based vaccines to induce CD8+ T cell responses4. Current efforts have focused on antigen delivery at the tissue and cellular levels, whereas subcellular delivery has been limited to facilitating antigen escape from lysosomes into the cytosol. In the absence of a small-sized high-affinity ER-targeting molecule, the importance of the 'last mile' from the cytosol to the ER remains elusive. Here we developed stimulator of interferon genes (STING) agonist-based ER-targeting molecules (SABER), which effectively deliver antigens to the ER and cluster key machinery in cross-presentation to form microreactors by folding the ER membrane. Conjugation of SABER to various antigens substantially enhances the induction of CD8+ T cell immune responses to tumour neoantigens and conserved viral epitopes, far exceeding that achieved by mixtures of antigens with STING agonists or conventional adjuvants. SABER also retains a potent adjuvant effect, effectively enhancing the ability of a SARS-CoV-2 subunit vaccine to induce broadly neutralizing antibodies. This study provides a high-affinity ER-targeting delivery system and vaccine adjuvant, demonstrating that precise subcellular delivery targeting the last mile of cross-presentation can lead to a qualitative leap.