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Lysosomal Cathepsin S Escape Facilitates Near Infrared Light-Triggered Pyroptosis Via an Antibody-Indocyanine Green
Fan Chen1,2, Xue-Fei Tian1,3, Teng Yang1,4
1Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310018, China.
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.
Insights
Near-infrared light triggers tumor-specific pyroptosis using antibody-bound indocyanine green. This novel approach generates reactive oxygen species, inducing cell death and potent antitumor immune responses, offering a new cancer therapy.
Area of Science:
- Biomedical Engineering
- Immunology
- Oncology
Background:
- Pyroptosis, a programmed cell death, shows therapeutic potential against tumors but lacks specific inducers.
- Current therapies face challenges due to tumor resistance to apoptosis.
Purpose of the Study:
- To develop a tumor-specific and controllable pyroptosis inducer for cancer therapy.
- To investigate the mechanism and efficacy of near-infrared light-triggered pyroptosis.
Main Methods:
- Utilized antibody-bound indocyanine green (ICG) for targeted delivery.
- Employed near-infrared light (NIR) to activate ICG, generating reactive oxygen species (ROS) within tumor cells.
- Analyzed the role of cathepsin S (CTSS) in cleaving gasdermin D (GSDMD) and inducing pyroptosis.
Main Results:
- Antibody-bound ICG successfully triggered pyroptosis specifically in tumors upon NIR irradiation.
- Excessive ROS generation led to lysosomal damage and cytosolic release of CTSS, which cleaved GSDMD independently of caspase-1.
- NIR-pyroptosis induced robust and lasting antitumor immune responses, enhancing efficacy with anti-PD-1 therapy.
Conclusions:
- Established NIR-pyroptosis as a non-apoptotic anticancer modality.
- Identified CTSS as a novel enzyme for GSDMD cleavage, crucial for pyroptosis induction.
- Demonstrated the potential of NIR-pyroptosis to overcome apoptosis resistance and synergize with immunotherapy.
