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However, fluoropyrimidine\u2010induced nucleotide imbalance is constrained by their metabolic instability. Here, we leverage ribonucleotides to amplify floxuridine (FUDR)\u2010induced mtDNA release and cGAS\u2013STING activation for enhanced cancer chemoimmunotherapy. We identified that cytidine monophosphate (CMP) significantly enhances FUDR\u2010mediated activation of the mtDNA\u2010driven cGAS\u2013STING pathway, inducing over 300\u2010fold upregulation of the interferon gene\n                    <jats:italic>Ifnb1<\/jats:italic>\n                    and initiating STING\u2010dependent antitumor immunity. Genome\u2010wide CRISPR\u2010Cas9 screening identified five pyrimidine\u2010metabolizing enzymes (CMPK1, CMPK2, TYMP, UPP1, and UPP2) that are responsible for the metabolic instability of floxuridine monophosphate (FdUMP). CMP and its intracellular metabolites can metabolically block these enzymes, thereby increasing the peak intracellular concentration of FdUMP by over 500\u2010fold and extending its half\u2010life by more than 20\u2010fold, which in turn promotes sustained intracellular nucleotide imbalance. To translate this mechanism into therapy, we co\u2010encapsulated FdUMP and CMP into hybrid lipid nanoparticles (FC\u2010NPs). FC\u2010NPs robustly activated STING\u2010dependent antitumor immunity, achieving remarkable therapeutic efficacy in multiple murine colorectal cancer (CRC) models. Our study not only addresses the long\u2010standing issue of fluoropyrimidine metabolic instability but also reveals a novel ribonucleotide\u2010mediated immunomodulatory mechanism, providing a promising strategy to potentiate chemoimmunotherapy in CRC.\n                  <\/jats:p>","DOI":"10.1002\/advs.77614","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T09:07:47Z","timestamp":1789981667000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ribonucleotides Amplify Mitochondrial DNA\u2010Driven cGAS\u2013STING Activation via FdUMP\u2010ribonucleotide Hybrid Particles to Potentiate Chemoimmunotherapy"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5294-6194","authenticated-orcid":false,"given":"Chao","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Affiliated Drum Tower Hospital, Medical School of Nanjing University Nanjing University  Nanjing China"},{"name":"Medical 3D Printing Center, Orthopaedic Institute, Department of Orthopaedic Surgery, School of Basic Medical Sciences, The First Affiliated Hospital Suzhou Medical College Soochow University  Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxuan","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Affiliated Drum Tower Hospital, Medical School of Nanjing University Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yesong","family":"Yao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Affiliated Drum Tower Hospital, Medical School of Nanjing University Nanjing University  Nanjing 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