Triple‐Microenvironment Decoding Enables Logic‐Unlocked Precision Photoimmunotherapy

Abstract

ABSTRACT Achieving tumor‐specific activation of pyroptosis and ferroptosis holds great promise for cancer immunotherapy, yet current photosensitizers (PSs) capable of such dual induction predominantly operate in an always‐on manner and rely on visible‐light excitation, limiting both precision and tissue penetration. Here, we report RPIB‐Cys , a self‐assembled triple‐locked near‐infrared (NIR) type‐I PS that remains photoinactive until activated in the mitochondrial microenvironment of triple‐negative breast cancer (TNBC). The molecule is intelligently engineered such that its photoactivity is restored only upon cooperative stimulation by elevated viscosity, alkaline pH, and high cysteine (Cys) levels, three hallmarks of cancer mitochondria. Unlocking simultaneously enables NIR fluorescence/photoacoustic (PA) imaging and efficient type‐I reactive oxygen species (ROS) generation. The resulting photoinduced oxidative stress triggers ferroptosis via glutathione depletion and glutathione peroxidase 4 (GPX4) inactivation, while concurrently inducing pyroptosis through gasdermin D (GSDMD) cleavage. This spatially controlled dual immunogenic cell death (ICD) converts cold TNBC into inflamed tumors, representing a multiple‑response activatable type‑I PS that uniquely integrates multimodal imaging with the concurrent induction of pyroptosis and ferroptosis for precision photoimmunotherapy.