Key Lab of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, P.R. China.
Beijing Institute for Brain Disorders, Beijing 100069, P.R. China.
Bioconjug Chem. 2020 Nov 18;31(11):2499-2503. doi: 10.1021/acs.bioconjchem.0c00522. Epub 2020 Nov 4.
Cyclic dinucleotides (CDNs), agonists of stimulator of interferon genes (STING), are promising agents for immunotherapy. However, the application of CDNs has been limited by their instability and low transmembrane efficiency. Here, we introduced a conjugated adjuvant of STING and TLR1/2, PamCSK-CDG. Conjugating CDG with PamCSK increased the stability and intracellular delivery. In addition, by synergistically activating the STING and TLR pathways, PamCSK-CDG was able to enhance immune activation. Both humoral and cellular immune responses were triggered by PamCSK-CDG plus OVA (V4), and tumor growth was significantly inhibited after V4 administration. More importantly, V4 can also boost the antigen-specific CD8+ T cell response for cancer cell killing. Thus, the conjugated STING and TLR1/2 agonist PamCSK-CDG can serve as a potent adjuvant for vaccine construction to augment antitumor immunotherapy.
环状二核苷酸（CDNs）是干扰素基因刺激物（STING）的激动剂，是免疫治疗的有前途的药物。然而，CDNs 的应用受到其不稳定性和低跨膜效率的限制。在这里，我们引入了 STING 和 TLR1/2 的共轭佐剂 PamCSK-CDG。将 CDG 与 PamCSK 缀合可提高稳定性和细胞内传递。此外，通过协同激活 STING 和 TLR 途径，PamCSK-CDG 能够增强免疫激活。 PamCSK-CDG 加 OVA（V4）可引发体液和细胞免疫反应，V4 给药后肿瘤生长明显受到抑制。更重要的是，V4 还可以增强针对癌细胞杀伤的抗原特异性 CD8+T 细胞反应。因此，共轭 STING 和 TLR1/2 激动剂 PamCSK-CDG 可用作疫苗构建的有效佐剂，以增强抗肿瘤免疫治疗。
