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However, its clinical utility is often hindered by the severe toxicity of chemotherapeutic agents and the immunosuppressive nature of the tumor microenvironment (TME). Herein, we engineer an injectable 5\u2010fluorouracil\u2010constituted DNA hydrogel embedded with quercetin (Q\u20105FDHG) through a novel DNA amplification reaction to navigate these impediments in a dual\u2010pronged manner. Q\u20105FDHG ensures progressive enzymatic degradation, which continuously releases 5\u2010fluorouracil (5FU) and quercetin (Que). Que attenuates the secretion of C\u2010C motif chemokine ligand 2 (CCL2), thereby reducing the recruitment of tumor\u2010associated macrophages and remodeling the immunosuppressive TME. Simultaneously, 5FU inhibits tumor cell proliferation with reduced systemic toxicity by optimizing local administration and induces immunogenic cell death (ICD) to enhance tumor immunogenicity. In orthotopic murine models of TNBC, Q\u20105FDHG exhibits remarkably specific anti\u2010tumor immune responses and boosts anti\u2010tumor efficacy, resulting in significant inhibition of tumor growth and lung metastasis. This study demonstrates a unique chemoimmunotherapy efficacy induced by the chemotherapeutic agent 5FU and small\u2010molecule compound Que from traditional Chinese medicine, and provides a safe and effective therapeutic strategy for TNBC with great promise for clinical translation.<\/jats:p>","DOI":"10.1002\/adhm.202503744","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T06:59:41Z","timestamp":1769497181000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A 5\u2010Fluorouracil\u2010Constituted DNA Hydrogel Embedded with Quercetin Remodels Tumor Microenvironment for Robust Chemoimmunotherapy"],"prefix":"10.1002","volume":"15","author":[{"given":"Yiping","family":"Li","sequence":"first","affiliation":[{"name":"Shanghai University of Traditional Chinese Medicine  Shanghai P. R. 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