Photothermal phase-responsive nanocomposites boost cGAS/STING-Driven antitumor immunity via mitochondrial DNA damage

A phase-change nanocomposite enables light-triggered multimodal therapy and tumor-localized cisplatin release. • Photothermal and photodynamic stress induces mitochondrial DNA damage and cytosolic DNA sensing. • Innate immune activation drives immunogenic cell death, dendritic cell priming, and CD8+ T-cell infiltration. • The treatment achieves durable control and helps overcome immune resistance in triple-negative breast cancer. Activation of the GMP/AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway can sensitize tumors to immunotherapy, yet conventional photothermal therapy (PTT) or photodynamic therapy (PDT) alone rarely generates enough cytosolic double-stranded DNA (dsDNA) to fully engage this axis. Here we develop phase-change lauric-acid nanocomposites (CCL NPs) that co-load photothermal Cu 2-X S nanoparticles and cisplatin. After cellular uptake, near-infrared (NIR) irradiation induces synergistic PTT/PDT, and NIR-II heating melts the lauric-acid shell to trigger on-demand cisplatin release within tumors. The resulting ROS burst together with cisplatin causes extensive mitochondrial DNA damage and dsDNA leakage into the cytosol, leading to robust cGAS/STING activation. In tumor-bearing mice, CCL NPs promote dendritic-cell maturation and antigen cross-presentation, increase cytotoxic T-lymphocyte infiltration, and elicit immunogenic cell death, achieving durable tumor suppression with minimal systemic toxicity. Released copper further contributes via cuproptosis. Overall, CCL NPs integrate controllable chemotherapy with PTT/PDT to amplify innate immune sensing and drive effective antitumor immunity. Download: Download high-res image (164KB) Download: Download full-size image