Cathepsin E (CTSE) is an intracellular aspartic protease with multifaceted roles in cancer biology and immune regulation 1. While traditionally implicated in antigen processing for MHC class II presentation, recent evidence reveals CTSE's prominent expression in cancer cells where it actively suppresses anti-tumor immunity. In hepatocellular carcinoma (HCC), CTSE-expressing cancer cells upregulate the ubiquinone signaling pathway, promoting des-γ-carboxy prothrombin (DCP) synthesis and release, which activates reactive oxygen species (ROS) production leading to T cell apoptosis and reduced CD3+ T cell infiltration 2. CTSE knockdown inhibits tumor growth and significantly enhances anti-PD-1 immunotherapy efficacy 2. In intrahepatic cholangiocarcinoma, co-localization of CTSE+ tumor cells with MARCO+ tumor-associated macrophages creates an immune-resistant microenvironment associated with poor prognosis 3. Functionally, CTSE promotes cancer cell proliferation through FAK/Paxillin/Akt signaling and correlates with extracellular matrix remodeling 4. CTSE serves as an independent prognostic risk factor in multiple cancers including pancreatic cancer, bladder cancer, and HCC 564. Its expression represents a potential therapeutic target, with CTSE-specific activity probes and photodynamic therapy approaches under investigation 1.