Tumor-targeted delivery of a STING agonist improves cancer immunotherapy

作者：Youtong Wu, Yan Fang, Wei Qi, Heping Shi, Huiling Tan, Yafang Deng, Zhiqun Zeng, Jian Qiu, Chuo Chen, Lijun Sun, Zhijian J. Chen · 发表于：Proceedings of the National Academy of Sciences · 年份：2022 · DOI：10.1073/pnas.2214278119 · 被引用次数：202 · 研究领域：interferon and immune responses、Viral Infections and Vectors、Ubiquitin and proteasome pathways

The cGAS-STING pathway is essential for immune defense against microbial pathogens and malignant cells; as such, STING is an attractive target for cancer immunotherapy. However, systemic administration of STING agonists poses safety issues while intratumoral injection is limited by tumor accessibility. Here, we generated antibody-drug conjugates (ADCs) by conjugating a STING agonist through a cleavable linker to antibodies targeting tumor cells. Systemic administration of these ADCs was well tolerated and exhibited potent antitumor efficacy in syngeneic mouse tumor models. The STING ADC further synergized with an anti-PD-L1 antibody to achieve superior antitumor efficacy. The STING ADC promoted multiple aspects of innate and adaptive antitumor immune responses, including activation of dendritic cells, T cells, natural killer cells and natural killer T cells, as well as promotion of M2 to M1 polarization of tumor-associated macrophages. These results provided the proof of concept for clinical development of the STING ADCs.