Overview

• Bone metastases secrete the protein DKK1 to convert neutrophils into an immature, CHI3L3-producing state that inhibits cytotoxic T cell function.
• In mouse models, DKK1 blockade caused neutrophils to mature, halted CHI3L3 production, and enabled anti-PD-1 therapy to shrink or eliminate bone tumors.
• The DKK1-blocking antibody DKN-01 has entered clinical trials as a potential combination partner for immune checkpoint inhibitors in patients with bone metastases.
• Researchers are developing CHI3L3-based biomarkers to identify patients with high neutrophil-mediated suppression and tailor DKK1-targeted treatments.
• This strategy underscores the emerging focus on modulating innate immune cells to overcome immunotherapy resistance in bone-colonizing lung, breast, and prostate cancers.