Sonodynamic activated nanoparticles with Glut1 inhibitor and cystine-containing polymer stimulate disulfidptosis for improved immunotherapy in bladder cancer

Disulfidptosis, a novel form of programmed cell death characterized by cystine accumulation and disulfide stress, primarily affects metabolically active tumors like bladder cancer, which is often considered to be a highly metabolic and energy-consuming tumor. However, translating disulfidptosis induction into clinical practice face substantial obstacles, including the limited solubility of key inducers, insufficient cystine buildup within cells, and cellular mechanisms regulating the NADP⁺/NADPH equilibrium. To fully unlock the therapeutic potential of disulfidptosis, a promising solution has emerged in the form of nanotechnology combined with sonodynamic therapy (SDT). This study reports a novel approach that enhances disulfidptosis through SDT, simultaneously promoting immunogenic cell death (ICD) and improving the immunosuppressive tumor microenvironment. The system, SPCP/CCP@Bay, comprises a degradable sonodynamic-pseudo-conjugate-polymer (SPCP) and a cystine-containing polymer (CCP), loaded with Bay-876. Following intravenous administration, SPCP/CCP@Bay effectively accumulates at tumor sites. Under ultrasound radiation, SPCP/CCP@Bay effectively releases Bay-876, disrupts the intracellular redox balance, releases cystine from CCP, and induces disulfidptosis. Moreover, SPCP/CCP@Bay induces ICD and synergizes with PD-1 monoclonal antibodies (α-PD-1) to suppress tumor growth. This integrated strategy holds significant promise in reshaping the tumor microenvironment, converting "cold tumors" to "hot tumors", and advancing the field of cancer immunotherapy.