中山大学王济研究组报道基于STING激动剂的ER靶向分子促进抗原交叉递呈。相关论文发表在2025年3月26日出版的《自然》杂志上。

在这里，研究小组开发了干扰素基因刺激剂（STING）受体激动剂基内质网靶向分子（SABER），它有效地将抗原传递到内质网，并通过折叠内质网膜形成交叉呈递的关键机制。SABER与多种肿瘤抗原的结合大大增强了CD8⁺ T细胞对肿瘤新抗原和保守病毒表位的免疫反应的诱导，远远超过了抗原与STING激动剂或常规佐剂的混合。SABER还保留了强有力的佐剂作用，有效增强了SARS-CoV-2亚单位疫苗诱导广泛中和抗体的能力。本研究提供了一种高亲和力的ER靶向递送系统和疫苗佐剂，表明靶向交叉呈递最后一英里的精确亚细胞递送可以带来质的飞跃。

据了解，CD8⁺ T细胞免疫反应对于对抗感染性疾病和肿瘤至关重要。抗原交叉呈递，主要发生在树突状细胞的内质网（ER），是蛋白质疫苗诱导CD8⁺ T细胞应答的必要条件。目前的研究主要集中在组织和细胞水平的抗原递送，而亚细胞递送则仅限于促进抗原从溶酶体逃逸到细胞质中。在缺乏小尺寸的高亲和力内质网靶向分子的情况下，从细胞质溶胶到内质网的“最后一英里”的重要性仍然是未知的。

附：英文原文

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

Author: 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

Issue&Volume: 2025-03-26

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.

DOI: 10.1038/s41586-025-08758-w

Source: https://www.nature.com/articles/s41586-025-08758-w