Abstract

Despite advances in oncology, the dual challenge of achieving precise tumor-targeted therapy while simultaneously activating antitumor immunity remains a major clinical barrier. In this study, we engineered a biocompatible copper-based platform, hyaluronic acid (HA) modified Cu ions based therapeutic (B-Cu/HA), that integrates selective tumor targeting, intrinsic cytotoxicity, and immune activation within a single therapeutic system. Leveraging the HA-CD44 interaction, B-Cu/HA exhibited preferential accumulation and prolonged retention in CD44-overexpressing tumors, while maintaining an excellent biosafety profile. Across multiple cancer models, B-Cu/HA robustly inhibited tumor progression. Mechanistically, it induced cuproptosis through upregulation of FDX1 and aggregation of lipoylated DLAT, and triggered ROS-mediated activation of the cGAS-STING pathway, promoting immunogenic cell death. Transcriptomic analysis revealed activation of hypoxia and cytokine signaling pathways, aligning with enhanced CD8+ T-cell cytotoxicity and remodeling of the tumor immune microenvironment. The animal models studies demonstrated that B-Cu/HA significantly suppressed tumor growth without systemic toxicity, and synergistically enhanced the efficacy of the immune checkpoint inhibitors anti-TIGIT. Together, these findings establish B-Cu/HA as a multifunctional, immunomodulatory formulation that offers a clinically translatable strategy to enhance tumor immunotherapy and overcome resistance in CD44-overexpressing tumors.