The novel PARP-1 inhibitor BMMP-TSC bridges mitochondrial dysfunction and innate immunity via mtDNA leakage and cGAS-STING to suppress breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options and an immunosuppressive tumor microenvironment. Novel PARP-1 inhibitors that combine direct cytotoxicity with innate immune activation hold great promise. Here we investigated the anti-breast cancer mechanism of a novel PARP-1 inhibitor, BMMP-TSC, focusing on mitochondrial damage-induced cGAS-STING activation. BMMP-TSC potently inhibited PARP-1 (IC50 = 59.85 nM) and formed a highly stable complex, as confirmed by 100 ns molecular dynamics simulations. In 4T1 TNBC cells, BMMP-TSC suppressed proliferation (IC50 = 25.6 μM), induced G2/M arrest, and triggered apoptosis. Mechanistically, BMMP-TSC caused mitochondrial membrane potential collapse, elevated mitochondrial ROS production, and promoted cytosolic release of mitochondrial DNA (mtDNA). This was accompanied by nuclear γH2AX foci formation and upregulation of cGAS, STING, and downstream cytokines (IFN-γ, IL-1β, IL-6, TNF-α) both at protein and mRNA levels. In a 4T1 xenograft model, BMMP-TSC (25 and 50 mg/kg) significantly suppressed tumor growth, reduced lung metastasis, increased CD80/CD86 expression, and shifted the Bax/Bcl-2 balance toward apoptosis, without causing overt toxicity in major organs. Collectively, these findings demonstrate that BMMP-TSC exerts potent anti-breast cancer activity by integrating PARP-1 inhibition, mitochondrial dysfunction, mtDNA leakage, and cGAS-STING-driven antitumor immunity. BMMP-TSC represents a promising next-generation PARP-1 inhibitor for immunochemotherapy of TNBC and other immunologically "cold" breast cancers.