Copper arsenite-loaded hydrogel for breast cancer therapy via cuproptosis-induced immunity synergized with arsenic chemotherapy.

Breast cancer remains a leading cause of cancer-related mortality. While arsenic trioxide (ATO) induces tumor cell apoptosis via oxidative stress, its clinical utility is constrained by systemic toxicity and a narrow therapeutic index. Immunotherapy, conversely, often shows limited efficacy in breast cancer, primarily due to its low tumor immunogenicity, immunosuppressive tumor microenvironment, and significant off-target toxicities. To address these challenges, we developed an in situ-forming alginate hydrogel co-loaded with copper arsenite nanoparticles (CuAs-PM@ALG) for localized chemo-immunotherapy. Upon intratumoral injection, the gel forms a sustained-release depot. Within the tumor, nanoparticles dissociate, releasing the chemotherapeutic component As to deplete glutathione and generate ROS, thereby inducing apoptosis and sensitizing tumor cells to immunotherapeutic component Cu2⁺-mediated cuproptosis, thereby synergistically amplifying immunogenic cell death (ICD). ICD activates dendritic cells and recruits cytotoxic T cells, reversing local immune suppression. Importantly, a synergistic cycle is established: arsenic-induced oxidative stress potentiates cuproptosis, while cuproptosis-driven immune activation enhances chemosensitivity. This bidirectional synergy promotes potent tumor clearance and establishes systemic anti-tumor immunity, effectively inhibiting growth. Comprehensive in vitro and in vivo studies validated the system's efficacy, safety, and mechanistic synergy, offering a novel and promising dual-targeting strategy for breast cancer therapy.