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

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 () and Ji Wang ()
Additional contact information
Xiafeng Wang: Sun Yat-sen University
Zhangping Huang: Sun Yat-sen University
Lixiao Xing: Fudan University
Liru Shang: Sun Yat-sen University
Juan Jiang: Sun Yat-sen University
Caiguanxi Deng: Sun Yat-sen University
Wei Yu: Sun Yat-sen University
Lin Peng: Sun Yat-sen University
Hao Yang: Liaoning University
Xiaohong Zheng: Sun Yat-sen University
Xinmin Liu: Sun Yat-sen University
Haolan Yang: Sun Yat-sen University
Yixin Chen: Sun Yat-sen University
Yongyong Li: Sun Yat-sen University
Jing Liu: Sun Yat-sen University
Xi Xie: Sun Yat-sen University
Wei Xu: Fudan University
Xiaojun Xia: Sun Yat-sen University Cancer Center
Zezhong Liu: Fudan University
Wanli Liu: China Ministry of Education Key Laboratory of Protein Sciences
Shibo Jiang: Fudan University
Yingyue Zeng: Liaoning University
Lu Lu: Fudan University
Ji Wang: Sun Yat-sen University

Nature, 2025, vol. 641, issue 8061, 202-210

Abstract: Abstract CD8+ T cell immune responses are critical for combating infectious diseases and tumours1–3. 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.

Date: 2025
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DOI: 10.1038/s41586-025-08758-w

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