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

Authors

Xueying Liu, Kejing Zhang, Yu Zhang, Yuejun Wang, Yuanjie Jiang, Qiao Duan, Liyan Fei, Juan Wei, Sheyu Zhang, Zhonglan Wang, Gaoyang Wang, Jianmin Wu, Yuzhi Luo, Yong Wei, Feng Ge, Lu Guo, Qin Wu

Published in

Oncogene. Oct 10, 2026. Epub Oct 10, 2026.

Abstract

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.

PMID:
42859190
Bibliographic data and abstract were imported from PubMed on 11 Oct 2026.

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