Overview

• Bone tumor–secreted DKK1 reprograms neutrophils into an immature, CHI3L3-producing phenotype that suppresses CD8+ T cell activity.
• DKK1 blockade in mouse models matures neutrophils, restores sensitivity to anti-PD-1 therapy and shrinks bone metastases, sometimes leading to complete tumor elimination.
• Patient serum and tumor analyses confirm elevated DKK1 levels in human bone metastases, underscoring the clinical relevance of preclinical findings.
• The DKK1-neutralizing antibody DKN-01 has entered human trials to evaluate its ability to enhance checkpoint inhibitor responses in patients with bone metastases.
• CHI3L3 expression and its gene signature are being developed as biomarkers to identify patients with neutrophil-driven immunosuppression and guide treatment selection.