Engineering STING Nanoadjuvants for spatiotemporally-tailored innate immunity stimulation and cancer vaccination therapy
Fangmin Chen, Huijuan Zhang, Shuang Li, Siyuan Ren, Lujia Huang, Zhixiong Cai, Lichen Yin, Mingyue Zheng, Xiaolong Liu, Zhiai Xu, Haijun Yu
Abstract
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. Spatiotemporally activating DC cells in lymph nodes (LN) for cancer vaccine therapy remains a challenge. Here the authors combine antigen loaded STING nanoadjuvants with LN-confined laser or ultrasound stimulation to activate DC cells, sequentially enhances antigen-specific CD8+ T cell response and reduces tumor size.