Nuclear PTK7 Interacts with DNA-PK Drives DNA Repair and Immune Evasion in Triple-negative Breast Cancer

PTK7, an evolutionarily conserved pseudokinase and a clinically relevant diagnostic and therapeutic target, has been detected in both membrane and nuclear compartments, but its nuclear function has not been elucidated. Here, we identify a critical role of nuclear PTK7 in coordinating DNA damage repair and regulating tumor immunogenicity in triple-negative breast cancer (TNBC).

Mechanistically, PTK7 interacts with DNA-PKcs to promote its activation and facilitate non-homologous end-joining (NHEJ). Loss of PTK7 impairs DNA repair and activates type I interferon signaling via cytosolic DNA accumulation, enhancing tumor immunogenicity. These effects are consistent across cellular and mouse tumors, and further validated in patient samples.