Fig. 8: Proposed mechanism of how tumor-intrinsic FOXM1 shapes the tumor microenvironment in cancers.

We propose that high levels of FOXM1 expression in cancer cells create an immunosuppressive microenvironment by promoting epigenetic silencing of the DNA-sensing protein STING, leading to reduced expression of stress ligands, MHC-1 class genes, and pro-inflammatory molecules. FOXM1 depletion leads to STING activation through several mechanisms. First, FOXM1 depletion leads to marked reductions in DNMT1 and UHRF1, constituting an epigenetic repressor complex targeted to the STING promoter. Second, FOXM1 depletion leads to an increase in micronuclei, likely through increased DNA damage or lapses in cell cycle, and consequently activation of the cytosolic DNA sensing cGas-STING-NFkB and unfolded protein response (UPR) pathways. Activation of STING-NFκB signaling induces expression of chemokines/cytokines such as CCL5, which in turn promotes recruitment of immune cells to the tumor. In addition, activation of STING-UPR stimulates expression of MHC1 and the stress ligand ULBP1, which facilitates interaction and activation of NKG2D-expressing CD8 + T and NK cells and subsequent killing of cancer cells. The model was created in BioRender. Nirzhor, S. (2025) https://BioRender.com/v49t420.