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

Abstract 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.