Pyrazolo[1,5-<i>a</i>]pyrimidine-Based Type-I Photosensitizer as an Efficient Pyroptosis Inducer for Tumor Ablation

Pyroptosis is a proinflammatory and lytic programmed cell death form, which can promote cytotoxic T lymphocyte (CTL) maturation and tumor infiltration through the release of damage-associated molecular patterns (DAMPs). Therefore, the induction of pyroptosis by small molecules is a promising strategy to activate antitumor immunity. In this work, we report the design of a new class of pyrazolo[1,5-<i>a</i>]pyrimidine-based type-I photosensitizers (PSs) as efficient pyroptosis inducers for cancer photodynamic therapy (PDT). Among the compounds, <b>ZS-3</b> exhibited the most excellent reactive oxygen species (ROS) generation ability and phototoxicity in vitro. It was found that <b>ZS-3</b> induced cell pyroptosis through the caspase-3/gasdermin E (GSDME) pathway under light irradiation, characterized by bubble formation and damage-associated molecular pattern release. Furthermore, <b>ZS-3</b> lipid nanoparticles significantly inhibited tumor growth and evoked antitumor immune responses in vivo.