DMAP1 Deficiency Suppresses Lung Cancer Progression by Destabilizing Replication Fork and Activating IFN Signaling-Mediated Anti-tumor Immunity

  • Adv Sci (Weinh). 2026 Jun;13(33):e17634. doi: 10.1002/advs.202517634.
Kan Huang  1  2  3  4 ,  Xi Dai  1 ,  Shuaihu Li  1 ,  Yingxue Chen  5 ,  Yaxin Yu  5 ,  Lin Wang  5 ,  Kun Liu  5 ,  Shuhan Lyu  6 ,  Chongyang Li  5  7 ,  Yihua Sun  2  3  4  8  9 ,  Fei Li  5
Affiliations
  • 1. Department of pathology, School of Basic Medical Sciences, Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.
  • 2. Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 3. Institute of Thoracic Oncology, Fudan University, Shanghai, China.
  • 4. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 5. Department of Pathology and Frontier Innovation Center, School of Basic Medicine Sciences, Shanghai Pudong Hospital, Fudan University, Shanghai, China.
  • 6. Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA.
  • 7. Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 8. Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 9. Shanghai Institute of Thoracic Oncology, Shanghai, China.
PMID: 41904944 DOI: 10.1002/advs.202517634
Abstract

Despite substantial progress in targeted and immune therapies, lung Cancer remains the leading cause of cancer-related mortality, highlighting the urgent need for novel therapeutic strategies. Through a CRISPR-based knock-out screen, we identified the DNA Methyltransferase 1-associated protein 1 (DMAP1) as a critical regulator of lung Cancer progression. Functional studies demonstrated that DMAP1 deficiency exerts its anti-tumor effects through attenuating tumor cell proliferation and activating T cell-mediated adaptive anti-tumor effects. Mechanistically, DMAP1 deficiency causes replication fork retardance, disturbs genome stability, and induces endogenous DNA damage, thereby activating IFN signaling-mediated anti-tumor immune response. Clinical data analyses revealed that high DMAP1 expression is associated with a "cold" tumor microenvironment and poorer overall survival in lung Cancer. These findings significantly advance our knowledge of DMAP1's function in lung Cancer development and offer a scientific basis for designing novel treatment approaches.

Keywords
DMAP1; IFN signaling; lung cancer; replication stress; tumor immunity.
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