DMAP1 promotes lung cancer progression by maintaining replication fork stability and suppressing IFN signaling-mediated anti-tumor immunity [CUT&Tag]

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 tumor progression. Functional studies showed that loss of DMAP1 exerts its anti-tumor effects through attenuating tumor cell proliferation and activating T cell-mediated adaptive anti-tumor effects. Mechanistically, loss of DMAP1 causes replication fork retardance, disturbs genome stability, and induces endogenous DNA damage, thereby activating tumor-intrinsic immune signaling and enhancing anti-tumor immune response during cancer cell growth. Clinical data analyses revealed that high DMAP1 expression is associated with reduced immune infiltration, 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.