CST4 (cystatin S) is a cysteine protease inhibitor encoded on chromosome 20 that functions as a non-competitive inhibitor of papain and ficin, with partial activity against stem bromelain and bovine cathepsin C 1. Beyond its canonical protease-inhibitory role, CST4 exhibits significant pathological functions in malignancy. In esophageal cancer, elevated CST4 expression promotes lymph node metastasis and tumor-associated lymphangiogenesis through VEGF-MAPK/ERK-MMP9/2 signaling, enhancing epithelial-mesenchymal transition, cell proliferation, and invasion 2. CST4 serves as a diagnostic and prognostic biomarker across multiple cancer types: serum CST4 demonstrates superior diagnostic performance for colorectal cancer (AUC 0.7739) compared to CEA and CA19-9, with combination models achieving AUC 0.941 for early detection 34. In gastric cancer, high CST4 expression independently predicts poor overall survival (HR=1.85) 5. CST4 also enhances diagnostic sensitivity for digestive system malignancies when combined with traditional tumor markers 6. Additionally, salivary CST4 functions as an antimicrobial and stress-response protein, becoming suppressed following high-intensity exercise alongside immunoglobulin changes 7. These findings establish CST4 as both a protease inhibitor and an emerging tumor-associated marker with potential therapeutic implications.