Xiafeng Wang, Zhangping Huang, Lixiao Xing, Liru Shang, Juan Jiang, Caiguanxi Deng, Wei Yu, Lin Peng, Hao Yang, Xiaohong Zheng, Xinmin Liu, Haolan Yang, Yixin Chen, Yongyong Li, Jing Liu, Xi Xie, Wei Xu, Xiaojun Xia, Zezhong Liu, Wanli Liu, Shibo Jiang, Yingyue Zeng, Lu Lu, Ji Wang
{"title":"STING agonist-based ER-targeting molecules boost antigen cross-presentation","authors":"Xiafeng Wang, Zhangping Huang, Lixiao Xing, Liru Shang, Juan Jiang, Caiguanxi Deng, Wei Yu, Lin Peng, Hao Yang, Xiaohong Zheng, Xinmin Liu, Haolan Yang, Yixin Chen, Yongyong Li, Jing Liu, Xi Xie, Wei Xu, Xiaojun Xia, Zezhong Liu, Wanli Liu, Shibo Jiang, Yingyue Zeng, Lu Lu, Ji Wang","doi":"10.1038/s41586-025-08758-w","DOIUrl":null,"url":null,"abstract":"<p>CD8<sup>+</sup> T cell immune responses are critical for combating infectious diseases and tumours<sup>1,2,3</sup>. Antigen cross-presentation, primarily occurring at the endoplasmic reticulum (ER) of dendritic cells, is essential for protein-based vaccines to induce CD8<sup>+</sup> T cell responses<sup>4</sup>. 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<sup>+</sup> 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.</p>","PeriodicalId":18787,"journal":{"name":"Nature","volume":"183 1","pages":""},"PeriodicalIF":50.5000,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1038/s41586-025-08758-w","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
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.
期刊介绍:
Nature is a prestigious international journal that publishes peer-reviewed research in various scientific and technological fields. The selection of articles is based on criteria such as originality, importance, interdisciplinary relevance, timeliness, accessibility, elegance, and surprising conclusions. In addition to showcasing significant scientific advances, Nature delivers rapid, authoritative, insightful news, and interpretation of current and upcoming trends impacting science, scientists, and the broader public. The journal serves a dual purpose: firstly, to promptly share noteworthy scientific advances and foster discussions among scientists, and secondly, to ensure the swift dissemination of scientific results globally, emphasizing their significance for knowledge, culture, and daily life.