XN@CuO/HA Nanobipyramids Trigger FOXO1-GADD45G-Mediated Cuproptosis and Synergy with Anti-PD-1 for Lung Cancer Therapy

Lung cancer is a leading cause of cancer-related mortality, with current therapies limited by drug resistance and immunosuppressive tumor microenvironment (TME). Cuproptosis offers new therapeutic prospects, but effective induction and targeted delivery remain challenging. Herein, we developed xanthohumol (XN)-coordinated copper oxide/hyaluronic acid (XN@CuO/HA) nanobipyramids as a novel cuproptosis inducer for non-small cell lung cancer (NSCLC) therapy. XN@CuO/HA exhibited good colloidal stability, and potent in vitro antitumor activity by inducing mitochondrial dysfunction, reactive oxygen species (ROS) accumulation, and cuproptosis. Mechanistically, transcriptomic and functional analyses identified the FOXO1-GADD45G axis as a critical mediator of XN@CuO/HA-induced cuproptosis. In vivo, XN@CuO/HA significantly suppressed LLC xenograft growth in C57BL/6 mice with excellent biosafety. Moreover, it remodeled the immunosuppressive TME by enhancing CD8 + T/NK1.1 + cell infiltration and reducing MDSCs, synergizing with anti-PD-1 antibody to achieve superior antitumor efficacy. Collectively, our findings highlight XN@CuO/HA as a safe and effective nano-therapeutic that induces FOXO1-GADD45G-mediated cuproptosis and potentiates immunotherapy, providing a promising combinatorial strategy for NSCLC treatment.