PO.TB10.16 · 肿瘤生物学
脱氧核糖环二核苷酸的化学调控STING激活型前药引发强效免疫激活和持久的抗肿瘤免疫
Chemically regulated STING-activating prodrugs of deoxyribose cyclic dinucleotides elicit robust immune activation and durable antitumor immunity
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摘要 Abstract
中文摘要
背景：源自脱氧核糖环二核苷酸（dCDN）的前药表现出增强的细胞通透性、稳定性和持续的STING激活。然而，磷酸三酯手性对其生物活性的影响仍未得到充分研究。本研究系统评估了炔基偶联、酯酶敏感的dCDN前药在体外和体内的立体化学依赖性药理学。方法：合成了dCDN前药的三种非对映异构体：(Rp,Rp)-10、(Sp,Sp)-10和(Rp,Sp)-10，通过手性HPLC纯化，并经NMR和HRMS确认。在THP1-Lucia ISG细胞中评估细胞摄取和稳定性。通过IFN-beta报告基因实验和phospho-TBK1/IRF3免疫印迹测定STING通路激活。在荷CT26结肠癌的BALB/c小鼠中经静脉给药评估体内疗效。通过肿瘤再攻击评估免疫记忆。结果：在这些异构体中，(Rp,Rp)-10表现出最强效的STING激活（EC50 = 1.7 nM）、更优的细胞摄取和延长的TBK1/IRF3信号。在小鼠中，所有三种前药诱导的全身细胞因子应答均强于ADU-S100或母体CDN 3',3'-c-di-dAMP。在CT26模型中，(Rp,Rp)-10在9/10只小鼠中实现完全肿瘤消退（90% CR），显著改善生存（p < 0.001），并建立了长期免疫记忆，再攻击时100%排斥。未观察到明显毒性。结论：磷酸三酯手性是dCDN前药活性的关键决定因素。(Rp,Rp)-10代表了一种有前景的下一代STING激动剂，具有强效的全身抗肿瘤免疫和持久的治疗效果。这些发现强调了立体化学控制在STING靶向癌症免疫治疗的合理设计中的重要性。
查看英文原文 English abstract
Background: Prodrugs derived from deoxyribose cyclic dinucleotides (dCDNs) exhibit enhanced cellular permeability, stability, and sustained STING activation. However, the impact of phosphotriester chirality on their bioactivity remains underexplored. This study systematically evaluates the stereochemistry-dependent pharmacology of alkyne-conjugated, esterase-sensitive dCDN prodrugs in vitro and in vivo. Methods: Three diastereoisomers of the dCDN prodrug: (Rp,Rp)-10, (Sp,Sp)-10, and (Rp,Sp)-10-were synthesized, purified by chiral HPLC, and confirmed by NMR and HRMS. Cellular uptake and stability were assessed in THP1-Lucia ISG cells. STING pathway activation was measured by IFN-beta reporter assays and phospho-TBK1/IRF3 immunoblots. In vivo efficacy was evaluated in CT26 colon carcinoma-bearing BALB/c mice following intravenous administration. Immune memory was assessed by tumor rechallenge. Results: Among the isomers, (Rp,Rp)-10 exhibited the most potent STING activation (EC50 = 1.7 nM), superior cellular uptake, and prolonged TBK1/IRF3 signaling. In mice, all three prodrugs induced stronger systemic cytokine responses than ADU-S100 or the parent CDN 3′,3′-c-di-dAMP. In the CT26 model, (Rp,Rp)-10 achieved complete tumor regression in 9/10 mice (90% CR), significantly improved survival (p < 0.001), and established long-term immunological memory with 100% rejection upon rechallenge. No overt toxicity was observed. Conclusion: Phosphotriester chirality is a critical determinant of dCDN prodrug activity. (Rp,Rp)-10 represents a promising next-generation STING agonist with potent systemic antitumor immunity and durable therapeutic effects. These findings underscore the importance of stereochemical control in the rational design of STING-targeted cancer immunotherapies.
利益披露 Disclosure
H. Liu, None..
Z. Xie, None..
K. Xu, None..
R. Xiang, None..
S. Li, None..
Z. Xi, None.