Manganese Vacancy-Engineered Prussian Blue Triggers Pyroptosis-Driven Innate Immunity for Second Near-Infrared Region Photoimmunotherapy

Synergistic activation of innate immunity and adaptive immunity provides a promising way to improve cancer immunotherapy, but achieving their precise and co-activation remains a major challenge. Here, we constructed a copper-doped manganese vacancy (V Mn )-engineered Prussian blue derivative (CuV Mn -PBA) as a dual functional pyroptosis-cyclic GMP-AMP synthase-stimulator of interferon genes signaling (cGAS-STING) activator for second near-infrared region (NIR-II) photoimmunotherapy. The V Mn induced by acid etching narrowed the bandgap and enhanced NIR-II absorption at 1060 nm, while Cu doping acted as electron-trapping sites to promote electron–hole separation, jointly boosting multienzymatic/photocatalytic activity. Under 1060 nm laser irradiation, this dual modification enabled robust reactive oxygen species (ROS) generation even in hypoxia. Excessive ROS-induced oxidative stress triggered gasdermin E-mediated tumor cell pyroptosis, driving mitochondrial DNA (mtDNA) release into the cytoplasm, which cooperated with dissociated Mn 2+ and pyroptosis-derived inflammatory factors to activate the cGAS-STING pathway. This cascade elevated tumor immunogenicity, promoted dendritic cells (DCs) maturation and cytotoxic T lymphocytes (CTLs) infiltration, and established long-term antitumor immune memory. In combination with αPD-1 checkpoint blockade, CuV Mn -PBA mediated complete primary tumor regression, suppressed distant tumor growth, and abrogated tumor recurrence, offering a promising paradigm for enhanced cancer photoimmunotherapy.