Photo-induced electron pumping meets nanozyme cascade: Triggering multimodal cell death for potent triple-negative...

Triple-negative breast cancer (TNBC) treatment is often hindered by tumor hypoxia, cellular survival compensation, and the immuno-suppressive micro-environment. Through the "molecular-electron pumping" strategy, a cyanine photosensitizer BrCy5 with excellent Type I ROS generation ability (two kinds of Type I ROS production of BrCy5 are 308% and 206% higher) was developed to realize photodynamic therapy-mediated immunotherapy under tumor hypoxia. In the work, a multifunctional nanoenzyme HMB loaded with Type I photosensitizer was further designed, which precisely delivers BrCy5 and Fe³⁺ to tumor cell mitochondria via tumor targeting and lysosomal endocytosis, triggering a lethal cascade of multimodal cell death. Released Fe³⁺ catalyzes endogenous H₂O₂ into O₂, relieving hypoxia to enhance photodynamic efficacy while depleting glutathione (GSH). Free BrCy5 accumulates in mitochondria, inducing severe mitochondrial dysfunction and lipid peroxidation via efficient ROS generation. This synergistic oxidative stress triggers ferroptosis, activates the Caspase-3/GSDME signaling axis for pyroptosis, leading to massive release of damage-associated molecular patterns (DAMPs) and potent immunogenic cell death (ICD). To enhance this cascade, System Xc^- inhibitor sulfasalazine (SSZ) was combined to further deepen GSH depletion and exacerbate ferroptosis. In bilateral tumor-bearing mice, this enhanced regimen created a highly inflamed microenvironment, promoting dendritic cells (DCs) maturation and cytotoxic T lymphocytes (CTLs) infiltration, reversing immunosuppression. Ultimately, it inhibited primary and distant tumor growth, converting "cold" to "hot" breast cancer, proposing a transformative strategy for efficient TNBC treatment by combining the "molecular-electron pumping" photosensitizer, multifunctional nanoenzyme carrier, and metabolic pathway blocking to induce multimodal tumor cell death-induced immunotherapy.