Clinically friendly smart hydrogel boosts cuproptosis and PD-L1 upregulation to enhance anti-tumor immunotherapy

Triple-negative breast cancer (TNBC) faces the challenge of limited treatment efficacy due to its highly invasive ability and its immunosuppressive microenvironment. This study found that cuproptosis, as an emerging therapeutic strategy, has unique therapeutic potential in TNBC. Nevertheless, the delivery difficulties of cuproptosis-inducing agents and the limited efficacy of single drugs restrict the clinical application of cuproptosis therapy. Herein, a temperature/pH dual-responsive composite hydrogel was developed to load Elesclomol-Cu (ES-Cu) and glucose oxidase (GOx) (ES-Cu&GOx@FFC). ES and Cu²⁺ can synergistically trigger cuproptosis in TNBC, and GOx can not only inhibit tumor metabolism by mediating glucose deprivation but also initiate the Fenton reaction by continuously generating H₂O₂ and synergizing with copper ions, driving a potent chemodynamic therapy (CDT). Furthermore, ES-Cu&GOx@FFC could significantly improve the immunosuppressive landscape and upregulate programmed death-ligand 1 (PD-L1) expression in TNBC. Combined therapy experiments showed that the combination treatment of ES-Cu&GOx@FFC and αPD-L1 achieved more than 90 % tumor volume regression. In summary, this study provides new insights into the therapeutic role of cuproptosis in TNBC, and integrates cuproptosis, starvation therapy, CDT, and immunotherapy through smart responsive hydrogels, providing an innovative solution for the treatment of TNBC.