Pyrazolo[1,5-a]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-a]pyrimidine-based type-I photosensitizers (PSs) as efficient pyroptosis inducers for cancer photodynamic therapy (PDT). Among the compounds, ZS-3 exhibited the most excellent reactive oxygen species (ROS) generation ability and phototoxicity in vitro. It was found that ZS-3 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, ZS-3 lipid nanoparticles significantly inhibited tumor growth and evoked antitumor immune responses in vivo.