CTSZ (cathepsin Z) is a cysteine-type peptidase that exhibits carboxy-monopeptidase and carboxy-dipeptidase activities 1, functioning primarily in lysosomes and extracellular matrices. Beyond its protease function, CTSZ plays critical roles in immune regulation and disease pathogenesis. In cancer, CTSZ defines an immunosuppressive macrophage subpopulation (APOE+CTSZ+TAM) in colorectal and lung cancers that exhibits anti-inflammatory characteristics and interacts with regulatory T cells 2. In prostate cancer, the CTSZ-TRA2A-IL32 axis promotes M2-macrophage infiltration and metastatic dissemination via proteasomal degradation of TRA2A, which alleviates suppression of IL32 splicing and subsequent IL-32 secretion 3. CTSZ overexpression associates with poor prognosis, advanced pathological staging, immune-enriched microenvironments, and elevated PD-1/PD-L1 expression 4. In tuberculosis, CTSZ functions at the host-pathogen interface within granuloma-associated macrophages. The conserved CTSZ-CXCL1 axis mediates TB severity; Ctsz ablation in mice increases bacterial burden and pulmonary inflammation, while CTSZ variants associate with TB disease severity in humans 56. In pulmonary arterial hypertension, CTSZ hypermethylation decreases mRNA levels and increases endothelial cell apoptosis 7. Additionally, CTSZ promotes multiple myeloma cell apoptosis through PDCD4-mediated translational regulation 8.