CST6 (cystatin E/M) is a secreted cysteine protease inhibitor that functions as a tumor suppressor and regulator of bone homeostasis. CST6 inhibits cathepsin L, cathepsin V, cathepsin K, cathepsin B, and legumain proteases 12. The protein plays a critical role in suppressing osteoclast differentiation and bone destruction by blocking cathepsin-mediated cleavage of NF-κB/p100 and TRAF3 following RANKL stimulation 2. In breast cancer, CST6 acts as a tumor suppressor that is frequently silenced through promoter hypermethylation, particularly in metastatic lesions (67% of lymph node metastases vs 27% of primary tumors) 3. CST6 suppresses breast cancer bone metastasis through the CST6-CTSB-SPHK1 signaling axis, where CST6 enters osteoclasts via endocytosis and inhibits CTSB activity 1. In multiple myeloma, elevated CST6 expression is associated with absence of osteolytic lesions and protects against bone disease 2. CST6 also modulates gene expression in breast cancer cells, notably down-regulating autotaxin, which contributes to its anti-proliferative and anti-invasive effects 4. Clinically, CST6-based therapeutics show promise for treating bone metastases and osteolytic diseases 15.