Membrane-tethered activation design of a photosensitizer boosts systemic antitumor immunity via pyroptosis

Pyroptotic immunogenic cell death presents an emerging targeting pathway for cancer immunotherapy. We report a novel membrane-tethered activation design of a photosensitizer (PS) that boosts systemic anti-tumor immunity to primary and distant tumors via pyroptosis induction. The membrane-tethered PS is designed by installing a new phenylbenzopyrylium PS with zwitterionic lipid anchors and a target-cleavable caging moiety. This design affords excellent membrane tethering and enzymatic activation of the PS, exerting specific phototoxicity to cancer cells and inducing effective pyroptosis. Our design demonstrates prolonged circulation, long-lasting fluorogenic imaging and persistent photodynamic therapy of immunogenic 'cold' tumors in vivo, eliciting potent immunity toward local and abscopal tumors via promoted maturation of dendritic cells and recruitment of cytotoxic T lymphocytes. This design affords a promising approach for enhancing systemic antitumor immunity for cancer immunotherapy.