Abstract Objective: This study investigates the role of transcription factor FOXM1 in creating an immune-suppressive tumor microenvironment (TME) by regulating stress ligands and the STING pathway in triple-negative breast cancer (TNBC). Methods: We performed in vitro and in vivo assays using CRISPR/Cas9-mediated knockout of FOXM1 in TNBC cell lines and syngeneic mouse models. Using single-cell RNA sequencing, we analyzed the impact of tumor-intrinsic FOXM1 on stress ligand expression and its downstream effects on immune cell interactions. FOXM1’s epigenetic regulation on STING pathway was further validated through chromatin immunoprecipitation. Results: We found tumor-intrinsic FOXM1 establishes an immune-suppressive TME by downregulating stress ligands like ULBP1 on cancer cells. This inhibition disrupts NKG2D-NKG2DL signaling, a key pathway for initiating natural killer and T cell cytotoxicity against cancer cells. FOXM1 achieves this by epigenetically silencing the DNA-sensor protein STING via a DNMT1-UHRF1 complex. Notably, patients with elevated FOXM1 and DNMT1 levels and reduced STING and ULBP1 levels show poorer survival rates and reduced responsiveness to immunotherapy. Conclusions: Our findings identify FOXM1 as a key regulator of immune evasion in TNBC, revealing a new pathway by which it shapes the TME through epigenetic repression. Targeting FOXM1 or its downstream effectors could enhance immunotherapy efficacy, offering new therapeutic strategies for patients with TNBC. Citation Format: J. Huang, D. Medina, D. Singh, S. Abdulsahib, P. Subbarayalu, T. Do, P. Prabhakar, J. Prochnau, M. Rao. Epigenetic silencing of DNA sensing pathway by FOXM1 blocks stress ligand-dependent anti-tumor immunity and immune memory in triple negative breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-13-05.
Huang et al. (2026) studied this question.