Combine antibody-drug conjugate with cmLumiOpto for triple-negative breast cancer treatment.

Triple-negative breast cancer (TNBC) is an aggressive and chemotherapy-resistant subtype characterized by high metastatic potential and frequent recurrence, making monotherapies largely ineffective. This study evaluates a combination strategy utilizing a CD276 (B7-H3)-targeted antibody-drug conjugate (ADC) alongside mitochondria-targeted gene therapy. The anti-CD276 monoclonal antibody-mertansine conjugate substantially reduces tumor burden at a low dose. It exhibits strong synergy with the cmLumiOpto platform, enhancing cytotoxicity across three TNBC cell lines, impairing mitochondrial function, and elevating the tumoral immune response. Furthermore, the ADC/cmLumiOpto combination suppresses TNBC metastasis in mouse models and inhibits tumor growth by 95%-100% in patient-derived xenograft models. Mechanistic investigations reveal downregulated metastatic signaling, tumor microenvironment remodeling, increased apoptosis, and upregulated tumoral immunity. Histological and body weight analyses indicate minimal systemic toxicity. These findings highlight the translational potential of combining CD276-targeted ADC with mitochondrial gene therapy to treat aggressive TNBC.