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

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.