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The study investigates how the chirality of dCDN prodrugs affects their immune activation and antitumor efficacy.

April 5, 2026Cancer Research0 citations

Abstract 7465: Chemically regulated STING-activating prodrugs of deoxyribose cyclic dinucleotides elicit robust immune activation and durable antitumor immunity

HLHuimin LiuSouthwest Petroleum University ZXZhiqiang XieNankai University KXKe XuNankai University

Key Points

The study investigates how the chirality of dCDN prodrugs affects their immune activation and antitumor efficacy.
Synthesis and purification of three dCDN prodrug diastereoisomers: (Rp,Rp)-10, (Sp,Sp)-10, and (Rp,Sp)-10.
Assessment of cellular uptake and stability in THP1-Lucia ISG cells.
Evaluation of STING pathway activation via reporter assays and immunoblots.
In vivo efficacy tested in CT26 colon carcinoma-bearing BALB/c mice after intravenous administration.
Assessment of immune memory through tumor rechallenge.
The (Rp,Rp)-10 isomer showed the highest STING activation potency with an EC50 of 1.7 nM.
All prodrugs induced stronger systemic cytokine responses compared to ADU-S100.
In the CT26 model, (Rp,Rp)-10 achieved 90% complete tumor regression and significantly improved survival (p < 0.001).
Long-term immunological memory was established with 100% tumor rejection upon rechallenge.
No significant toxicity was reported.

Abstract

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-β 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. Citation Format: Huimin Liu, Zhiqiang Xie, Kejia Xu, Rong Xiang, Shibo Li, Zhen Xi, . Chemically regulated STING-activating prodrugs of deoxyribose cyclic dinucleotides elicit robust immune activation and durable antitumor immunity abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7465.

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