Pyroptosis-Inducing Nanoplatform with Plasmonic-Enhanced Phototherapy for Metastasis-Suppressive Cancer Immunotherapy

The immunosuppressive microenvironment of solid tumors limits the efficacy of conventional therapies and promotes tumor metastasis. Reprogramming this hostile microenvironment through pyroptosis-mediated immunotherapy represents a promising strategy to activate systemic antitumor immunity. Herein, we developed a plasmonic-enhanced nanoplatform by engineering tumor-targeting RGD peptide and photosensitizer onto plasmonic nanoparticles, creating a potent pyroptosis inducer. This nanoconstruct exhibits enhanced photothermal conversion efficiency and photostability compared with free photosensitizers, addressing critical limitations in photodynamic therapy. The nanoplatform preferentially accumulates in mitochondria of breast cancer cells, where laser irradiation triggers robust reactive oxygen species (ROS) generation and subsequent gasdermin E (GSDME)-dependent pyroptosis. In 4T1 tumor-bearing mice, the nanoplatform demonstrated superior tumor targeting and penetration. Laser activation induced immunogenic pyroptosis, releasing damage-associated molecular patterns (DAMPs) that promoted dendritic cell maturation and cytotoxic T lymphocyte infiltration. Moreover, this approach not only suppressed primary and distant tumor growth but also inhibited pulmonary and liver metastasis through the establishment of long-term immune memory. By synergizing plasmonic-enhanced phototherapy with pyroptosis-mediated immunotherapy, this nanoplatform overcomes key limitations of current photodynamic therapies while providing a powerful strategy for metastasis-suppressive cancer treatment.