Activation of pyroptosis by specific organelle-targeting photodynamic therapy to amplify immunogenic cell death for anti-tumor immunotherapy

Pyroptosis, a unique lytic programmed cell death, inspired tempting implications as potent anti-tumor strategy in pertinent to its potentials in stimulating anti-tumor immunity for eradication of primary tumors and metastasis. Nonetheless, rare therapeutics have been reported to successfully stimulate pyroptosis. In view of the intimate participation of reactive oxygen species (ROS) in stimulating pyroptosis, we attempted to devise a spectrum of well-defined subcellular organelle (including mitochondria, lysosomes and endoplasmic reticulum)-targeting photosensitizers with the aim of precisely localizing ROS (produced from photosensitizers) at the subcellular compartments and explore their potentials in urging pyroptosis and immunogenic cell death (ICD). The subsequent investigations revealed varied degrees of pyroptosis upon photodynamic therapy (PDT) towards cancerous cells, as supported by not only observation of the distinctive morphological and mechanistic characteristics of pyroptosis, but for the first-time explicit validation from comprehensive RNA-Seq analysis. Furthermore, in vivo anti-tumor PDT could exert eradication of the primary tumors, more importantly suppressed the distant tumor and metastatic tumor growth through an abscopal effect, approving the acquirement of specific anti-tumor immunity as a consequence of pyroptosis. Hence, pyroptosis was concluded unprecedently by our proposed organelles-targeting PDT strategy and explicitly delineated with molecular insights into its occurrence and the consequent ICD. [Display omitted] •Precise and specific organelle-targeting photosensitizers (mitochondria, lysosomes and endoplasmic reticulum) was synthesized.•The pyroptosis rates were much higher following mitochondria and endoplasmic reticulum-targeting photodynamics therapy in vitro.•Mitochondria and endoplasmic reticulum-targeting photodynamics therapy inhibited tumor progression by inducing pyroptosis in vivo.•Immune memory effect following specific organelle-targeting photodynamics therapy suppressed tumor metastasis in vivo.