Mitochondria-Targeting\nAIEgens as Pyroptosis Inducers\nfor Boosting Type‑I Photodynamic Therapy of Tongue Squamous\nCell Carcinoma

The development of a photosensitizer (PS) that induces\npyroptosis\ncould be a star for photodynamic therapy (PDT), particularly with\ntype-I PSs that produce reactive oxygen species (ROS) in a hypoxic\ntumor microenvironment. Since pyroptosis is a recently characterized\ncell death pathway, it holds promise for advancing PDT in oncology,\nwith PSs playing a critical role. Herein, we develop a PS named Th-M\nwith aggregation-induced emission (AIE) characteristics for type-I\nPDT against tongue squamous cell carcinoma (TSCC). Th-M stands out\nfor its exceptional mitochondrial-targeting ability, which triggers\nmitochondrial dysfunction and leads to Caspase-3 and Gasdermin E (GSDME)\ncleavage under white light irradiation, inducing pyroptosis in TSCC\ncells. Our studies verify the effectiveness of Th-M in destroying\ncancer cells in vitro and suppressing tumor growth in vivo while also\ndemonstrating a favorable biosafety profile. This work pioneers the\napplication of Th-M as a mitochondria-targeted, type-I PS that leverages\nthe mechanism of pyroptosis, offering a potent approach for the treatment\nof TSSC with promising implications for future PDT of cancers.