PTK7 scaffolds DNA-PKcs to promote DNA damage response and immune evasion in triple-negative breast cancer.

Membrane proteins with nuclear localization often exert non-canonical functions. PTK7, an evolutionarily conserved pseudokinase and a prominent therapeutic target, is primarily recognized for its cell-surface signaling; however, its intracellular role in tumor biology remains unclear. Here, we identify a previously unrecognized role of PTK7 in coordinating DNA damage response and tumor immune response in triple-negative breast cancer (TNBC). Mechanistically, PTK7 translocates to the nucleus where it associates with DNA-dependent protein kinase (DNA-PKcs), acting as a molecular scaffold to enhance its kinase activation and facilitate non-homologous end-joining (NHEJ) repair. Loss of PTK7 impaired DNA-PKcs-associated non-homologous end-joining (NHEJ) repair, increased double-strand breaks, and subsequent activation of the STING-IFN axis. Furthermore, PTK7 deficiency significantly sensitizes TNBC tumors to anti-PD-1 therapy in vivo. Clinically, high PTK7 expression correlates with suppressed immune signatures and poor immunotherapy response in TNBC patients. Together, our findings uncover a PTK7-associated DNA repair and immune-evasion program in TNBC and nominate PTK7 as a potential biomarker and therapeutic target for improving immunotherapy response.