Ultrasound-activated Cu2−XSe/TiO2 heterostructured nanosonosensitizer enables coordinated induction of ferroptosis and cuproptosis for tumor immunotherapy

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive subtype characterized by the absence of actionable molecular targets, high metastatic propensity, and limited responsiveness to current immunotherapies. Although immune checkpoint inhibitors show promise, their clinical efficacy is constrained by low tumor immunogenicity and a highly immunosuppressive tumor microenvironment (TME). This study reports a hyaluronic acid (HA)-functionalized TiO2@Cu2–XSe@HA nanosystem that promotes the coordinated induction of ferroptosis and cuproptosis, thereby enhancing sonodynamic immunotherapy against TNBC. It features a rationally designed Cu2–XSe/TiO2 heterostructured nanosonosensitizer and an integrated therapeutic strategy combining ultrasound-activated sonodynamic effects with the coordinated induction of ferroptosis and cuproptosis. Under ultrasound irradiation, the Cu2−XSe/TiO2 heterointerface promotes efficient electron transfer and reactive oxygen species (ROS) generation, markedly amplifying sonodynamic efficacy. Meanwhile, released Cu2+ depletes intracellular glutathione, disrupts redox homeostasis, thereby promoting copper-dependent proteotoxic stress. In parallel, Cu2+ induces autophagic degradation of glutathione peroxidase 4, further enhancing ferroptotic signaling. This coordinated induction effectively suppresses tumor growth, remodels the immunosuppressive TME, and potentiates antitumor immunity, as further corroborated by single-cell RNA sequencing. Collectively, this study provides a rational strategy for integrating sonodynamic therapy with dual non-apoptotic cell death pathways, offering a promising strategy to sensitize TNBC to immunotherapy.