环状二核苷酸免疫刺激剂-适配体偶联物增强STING驱动抗肿瘤免疫研究

Abstract

Activation of the stimulator of interferon genes (STING) pathway has emerged as a promising approach in cancer immunotherapy. Although cyclic dinucleotide (CDN)-based STING agonists have demonstrated considerable antitumor potential in preclinical studies, their clinical translation has been hampered by multiple limitations, including poor metabolic stability, low cellular uptake, limited tumor accumulation, and off-target toxicity. To address these challenges, we developed a tumor-targeting immune stimulator-aptamer conjugate (ISApC) by conjugating the phosphorothioate isomer of CDN (F2) to an aptamer Sgc8c via a cleavable linker (F2-L1-Sgc8c). Compared to free F2 or non-targeting conjugate, F2-L1-Sgc8c induced more efficient STING pathway activation via specific binding and efficient internalization by targeted cells, and improved pharmacokinetic profile in the blood. Moreover, in the 4T1 murine breast cancer model, systemic administration of F2-L1-Sgc8c effectively accumulated in tumors, inhibited tumor proliferation, better immune safety, and synergized with the immune checkpoint inhibitor anti-PD-1 antibody by intensively stimulating anticancer immune response. The combination therapy significantly increased the number of mature dendritic cells and CD8 + /CD4 + T cell ratio, remodeling the tumor immune microenvironment. Together, the ISApC represents a promising strategy for targeted STING agonist delivery, with potential to broaden the clinical applicability of STING-based immunotherapy. Download: Download high-res image (143KB) Download: Download full-size image