<p>Triple-negative breast cancer (TNBC) remains a formidable clinical challenge because of its high aggressiveness, metastatic potential, and lack of effective therapeutic options. In this study, we developed an injectable multifunctional hydrogel, MND-ART-GEL, by encapsulating immunostimulatory manganese urate (MnUA), the chemotherapeutic agent doxorubicin (DOX), and an artemisinin derivative, artesunate (ART), within a thermosensitive Pluronic F127 matrix. Uric acid crystals (MSU) and manganese ions (Mn²⁺) were coordinated and assembled into manganese urate (MnUA). The MSU–Mn²⁺ system exhibits a synergistic immunoactivating effect by combining the DAMP-like immune stimulation of MSU with the STING pathway activation ability of Mn²⁺. Owing to its simple chemical composition, low cost, and accessibility, this combination offers a more practical and scalable alternative to conventional synthetic immune agonists. ART synergizes with DOX to exert potent antitumor effects. MND-ART-GEL synergistically elevated intracellular ROS levels, inducing oxidative stress, mitochondrial damage, and subsequent tumor cell apoptosis, immunogenic cell death (ICD), and exposure to immune markers such as MHCI and Fas. Moreover, MND-ART-GEL downregulated STAT3 expression, thereby suppressing tumor cell invasion and migration. In orthotopic and postsurgical TNBC mouse models, MND-ART-GEL significantly inhibited tumor growth and recurrence, remodeled the immunosuppressive tumor microenvironment, enhanced CD8⁺ T-cell infiltration, dendritic cell maturation, and M1 macrophage polarization, reduced PD-1/PD-L1 expression on CD8⁺ T cells, and promoted the secretion of immune-related cytokines. This study presents a localized drug delivery strategy that integrates chemotherapy, immune modulation, and multitarget synergy, offering a promising approach to overcome therapeutic resistance and reduce recurrence in TNBC.</p> Graphical Abstract <p></p>