2. Academic Validation
  3. STING agonist-based ER-targeting molecules boost antigen cross-presentation

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

  • Nature. 2025 May;641(8061):202-210. doi: 10.1038/s41586-025-08758-w.
Xiafeng Wang # 1 2,  Zhangping Huang # 2,  Lixiao Xing # 3,  Liru Shang # 2,  Juan Jiang # 2,  Caiguanxi Deng 2,  Wei Yu 2,  Lin Peng 2,  Hao Yang 4,  Xiaohong Zheng 2,  Xinmin Liu 2,  Haolan Yang 2,  Yixin Chen 2,  Yongyong Li 2,  Jing Liu 2,  Xi Xie 5,  Wei Xu 3,  Xiaojun Xia 6,  Zezhong Liu 7,  Wanli Liu 8,  Shibo Jiang 3,  Yingyue Zeng 9,  Lu Lu 10,  Ji Wang 11
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 2 Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 3 Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Fudan University, Shanghai, China.
  • 4 School of Life Sciences, Liaoning University, Shenyang, China.
  • 5 State Key Laboratory of Optoelectronic Materials and Technologies, Guangdong Province Key Laboratory of Display Material and Technology, School of Electronics and Information Technology, Sun Yat-sen University, Guangzhou, China.
  • 6 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 7 Department of Pharmacology and the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China.
  • 8 State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing, China.
  • 9 School of Life Sciences, Liaoning University, Shenyang, China. zengyingyue@lnu.edu.cn.
  • 10 Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Fudan University, Shanghai, China. lul@fudan.edu.cn.
  • 11 Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. wangj683@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 40140567 DOI: 10.1038/s41586-025-08758-w
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.

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