Programable Prodrug Nanomodulator Targets Tumor Redox Homeostasis Imbalance to Amplify Disulfidptosis and Immunogenic Pyroptosis for Breast Tumor Immunotherapy

The Pro@FLNC prodrug-based nanoplatform synergistically integrates photodynamic therapy (PDT) with disulfidptosis to induce metabolic collapse in tumor cells. By generating reactive oxygen species (ROS) and disrupting redox balance, it triggers caspase-mediated pyroptosis, amplifies immunogenic cell death, reshapes the tumor microenvironment, and enhances antitumor immunity, offering a potent strategy for targeted cancer therapy and immune activation.

Abstract

Despite the great potential of photodynamic therapy (PDT), its success remains compromised by the abnormal redox homeostasis of tumor cells, which supports survival, growth, and resistance to oxidative therapeutic interventions by neutralizing reactive oxygen species (ROS). To overcome this barrier, a multifunctional prodrug nanomodulator (Pro@FLNC) is designed to induce disulfidptosis and immunogenic pyroptosis to trigger an antitumor immune response. Pro@FLNC features a prodrug core–shell structure where ursolic acid (UA) and Chlorin e6 (Ce6) are conjugated via a GSH-responsive linker and encapsulated in a DSPE-PEG-FA lipid shell for enhanced stability, biocompatibility, and tumor-specific targeting. Within the tumor microenvironment (TME), Pro@FLNC depletes intracellular GSH, disrupts redox homeostasis, and releases Ce6 and UA, triggering oxidative stress and mitochondrial dysfunction. These mechanisms amplify ROS production, promote lipid peroxidation, and initiate disulfidptosis, evidenced by increased SLC7A11 expression and F-actin collapse. Elevated ROS levels and metabolic imbalance-triggered disulfidptosis further activate immunogenic pyroptosis, releasing damage-associated molecular patterns (DAMPs) that stimulate dendritic cell maturation and cytotoxic T-cell activation. Together, Pro@FLNC reshapes the TME, reduces immunosuppressive cells, and promotes CD8⁺ T-cell infiltration, effectively suppressing primary tumors and metastases. This programmed prodrug nanomodulator offers a promising strategy to enhance PDT and immunotherapy for advanced breast cancer.