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

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

  • Adv Sci (Weinh). 2025 Jun 20:e04851. doi: 10.1002/advs.202504851.
Fan Chen 1 2,  Xue-Fei Tian 1 3,  Teng Yang 1 4,  Yu-Jie Dai 5,  Da-Yuan Chen 6,  Hong-Bo Chen 6,  Takaya Shimura 7,  Xin-Fang Li 5,  Chu-Lin Sha 1,  Qing Ji 8,  Jun Cao 8,  Mei-Yu Fang 8,  Jin-Biao Shang 1,  Jian-Min Fang 9,  Ye Lu 1,  Wei-Hui Zheng 1,  Peng Guo 1 3,  Wei-Hong Tan 1 3
Affiliations

Affiliations

  • 1 Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310018, China.
  • 2 Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan, 410082, China.
  • 3 School of Molecular Medicine, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, 310024, China.
  • 4 College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China.
  • 5 MabPlex International, Yantai, Shandong, 264006, China.
  • 6 Guilin University of Electronic Technology, Guilin, Guangxi, 541004, China.
  • 7 Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601, Japan.
  • 8 Department of Head and Neck and Rare Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China.
  • 9 School of Life Science and Technology, Tongji University, Shanghai, 200092, China.
PMID: 40539828 DOI: 10.1002/advs.202504851
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.

Keywords

antibody‐drug conjugate; anti‐tumor immunity; pyroptosis.

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