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Chem. J. Chinese Universities

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Incorporation of 5-Fluoro-2'-Deoxyuridine (FdU) into DNA Enhances cGAS-Mediated Immune Responses

MA Jingke1, GUAN Wenli1, ZHOU Yongchang1, Yu Zhilei1, HANG Hai1, ZHANG Hanwen1, REN Mengtian2,3*, ZHOU Chuanzheng1*   

  1. 1. State Key Laboratory of Elemento-Organic Chemistry, Frontiers Science Center for New Organic Matter, Department of Chemical Biology, College of Chemistry, Nankai University 2. School of Chemistry, Tiangong University 3. Cangzhou Institute of Tiangong University,
  • Received:2026-05-28 Revised:2026-06-18 Online First:2026-06-21 Published:2026-06-21
  • Supported by:
    Supported by the National Key Research and Development Program of China (No. 2025YFA0920900), the National Natural Science Foundation of China (Nos. 92581104, 22377059 and 22407100), the Natural Science Foundation of Tianjin (No. 25ZXWCSY00100) and the Hebei Natural Science Foundation (No. B2025110005)

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Abstract: In this study, we synthesized 5-fluoro-2′-deoxyuridine (FdU)-modified dsDNA and systematically evaluated how FdU modification affects its ability to activate the innate immune receptor cyclic GMP–AMP synthase (cGAS). FdU-modified dsDNA exhibited increased binding affinity for cGAS and enhanced cGAS-dependent 2′,3′-cGAMP production in vitro. In both murine and human immune cells, FdU-modified dsDNA elicited stronger type I interferon and pro-inflammatory responses through activation of the cGAS, with response magnitude positively correlating with the number of FdU substitutions. These findings establish a potential immunological link between fluoropyrimidine chemotherapy and antitumor immunity, and highlight FdU modification as a promising strategy for engineering potent cGAS agonists for immunotherapeutic applications.

Key words: DNA modification, Fluoropyrimidine; Immunotherapy

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