Epigenetic silencing of DNA sensing pathway by FOXM1 blocks stress ligand-dependent antitumor immunity and immune memory.

ABSTRACT: The interplay between tumor cells and the microenvironment significantly influences cancer progression. Here, we report a significant role of the transcription factor FOXM1 in shaping the tumor immune landscape. Single-cell sequencing reveals that tumor-intrinsic FOXM1 creates an immune-suppressive tumor microenvironment by inhibiting expression of stress ligands (including ULBP1) on cancer cells, thereby blocking NKG2D-NKG2DL interactions critical for priming natural killer- and T cell-mediated cytotoxicity of cancer cells. FOXM1 suppresses ULBP1 expression by epigenetically silencing the DNA-sensing protein STING using a DNMT1-UHRF1 complex, which in turn inhibits the unfolded protein response protein CHOP from activating ULBP1. Importantly, cancer patients with higher levels of FOXM1 an

SUBMITTER: Timilsina S 

PROVIDER: S-EPMC12037779 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature