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