Lysosomal Cathepsin S Escape Facilitates Near Infrared Light-Triggered Pyroptosis Via an Antibody-Indocyanine Green Conjugate.

Pyroptosis is a proinflammatory programmed cell death (PCD) that is causally linked to antitumor immune responses, but the therapeutic potential of pyroptosis has been limited by the lack of tumor-specific and controllable inducers. Here, it is reported that tumor-specific pyroptosis can be spatiotemporally triggered via near-infrared light (NIR-pyroptosis) by using an antibody-bound indocyanine green (ICG), a clinically approved and nontoxic fluorescent dye. Mechanistically, the key molecular steps are identified by which antibody-bound ICG generates excessive reactive oxygen species (ROS) within lysosomes after internalization, leading to lysosomal membrane damage and the cytosolic release of cathepsin S (CTSS), which cleaves gasdermin D (GSDMD), IL-18, and IL-1β independently of caspase-1, and thereby induces pyroptosis, while other cathepsin family members fail to cleave GSDMD. Functionally, in both ICAM1+ and HER2+ solid tumors, antibody-bound ICG-mediated NIR-pyroptosis triggers potent and durable antitumor immune responses through the release of proinflammatory cytokines. Furthermore, NIR-pyroptosis synergize with anti-PD-1 therapy by activating adaptive immune cells via upregulated IFN-γ secretion. The findings identify CTSS as a novel enzyme for GSDMD cleavage and establish NIR-pyroptosis as a non-apoptotic anticancer modality, providing a promising opportunity to overcome apoptosis resistance in current cancer therapies.