A 5‐Fluorouracil‐Constituted DNA Hydrogel Embedded with Quercetin Remodels Tumor Microenvironment for Robust Chemoimmunotherapy

Chemoimmunotherapy has emerged as a promising treatment modality for triple-negative breast cancer (TNBC). 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-fluorouracil-constituted DNA hydrogel embedded with quercetin (Q-5FDHG) through a novel DNA amplification reaction to navigate these impediments in a dual-pronged manner. Q-5FDHG ensures progressive enzymatic degradation, which continuously releases 5-fluorouracil (5FU) and quercetin (Que). Que attenuates the secretion of C-C motif chemokine ligand 2 (CCL2), thereby reducing the recruitment of tumor-associated 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-5FDHG exhibits remarkably specific anti-tumor immune responses and boosts anti-tumor 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-molecule compound Que from traditional Chinese medicine, and provides a safe and effective therapeutic strategy for TNBC with great promise for clinical translation.