Chen Fangmin, Zhang Huijuan, Li Shiqin, Ren Siyuan, Huang Lujia, Cai Zhixiong, Yin Lichen, Zheng Mingyue, Liu Xiaolong, Xu Zhiai, Yu Haijun
State Key Laboratory of Chemical Biology & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Nat Commun. 2025 Jul 1;16(1):5773. doi: 10.1038/s41467-025-60927-7.
Spatiotemporally-tailored activation of dendritic cells (DC) in lymph nodes (LN) remains a critical challenge for effective cancer vaccination therapy. In this study, we show that photo/sonodynamic effect can trigger the nuclear transcription factor-kappa B (NF-κB) and stimulator of interferon genes (STING) pathways activation in DC. We engineers a library of spatiotemporally-tailored STING nanoadjuvants (SNA) by conjugating the photo/sonosensitizer and STING agonist onto the biodegradable polypeptide, and co-assembling with charge-modified polypeptides. The combination of antigen-loaded SNA vaccine (SNVac) with laser irradiation or ultrasound stimulation (namely SNVac-L or SNVac-US) efficiently facilitates DC activation and induces antigen-specific CD8 T cell response in vivo comparing to the free mixture of antigen with STING agonist. We further demonstrate that SNVac-L monotherapy or combination therapy with immune checkpoint blockade (ICB) elicits antitumor immunity to reduce tumor size and prevent tumor relapse in multiple mouse tumor models. This study thus provides a potential translational strategy for spatiotemporally-tailored innate immunity stimulation of DC to potentiate cancer immunotherapy.
在淋巴结（LN）中对树突状细胞（DC）进行时空定制激活仍然是有效癌症疫苗治疗面临的一项关键挑战。在本研究中，我们表明光/声动力效应可触发DC中的核转录因子-κB（NF-κB）和干扰素基因刺激因子（STING）通路激活。我们通过将光/声敏剂和STING激动剂缀合到可生物降解多肽上，并与电荷修饰多肽共同组装，构建了一个时空定制的STING纳米佐剂（SNA）文库。与抗原与STING激动剂的游离混合物相比，负载抗原的SNA疫苗（SNVac）与激光照射或超声刺激（即SNVac-L或SNVac-US）的组合在体内有效促进DC激活并诱导抗原特异性CD8 T细胞反应。我们进一步证明，SNVac-L单药治疗或与免疫检查点阻断（ICB）联合治疗可引发抗肿瘤免疫，以减小多种小鼠肿瘤模型中的肿瘤大小并预防肿瘤复发。因此，本研究为时空定制DC的固有免疫刺激以增强癌症免疫治疗提供了一种潜在的转化策略。
