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

Santosh Timilsina, Jian Yu Huang, Nourhan Abdelfattah, Daisy Medina, Deepika Singh, Shahad Abdulsahib, Panneerdoss Subbarayalu, Trong Phat Do, Prabhakar Pitta Venkata, Saif Nirzhor, Jack Prochnau, Mukund Bhandari, Siyuan Zheng, Yidong Chen, Gang Huang, Neelam Mukherjee, Robert Hromas, Patrick Sung, Virginia Kaklamani, Ratna Vadlamudi, Nu Zhang and Manjeet K. Rao ()
Additional contact information
Santosh Timilsina: Greehey Children’s Cancer Research Institute
Jian Yu Huang: Greehey Children’s Cancer Research Institute
Nourhan Abdelfattah: Houston Methodist Research Institute
Daisy Medina: Greehey Children’s Cancer Research Institute
Deepika Singh: Greehey Children’s Cancer Research Institute
Shahad Abdulsahib: Greehey Children’s Cancer Research Institute
Panneerdoss Subbarayalu: Greehey Children’s Cancer Research Institute
Trong Phat Do: Greehey Children’s Cancer Research Institute
Prabhakar Pitta Venkata: Greehey Children’s Cancer Research Institute
Saif Nirzhor: Greehey Children’s Cancer Research Institute
Jack Prochnau: Greehey Children’s Cancer Research Institute
Mukund Bhandari: UT Southwestern Medical Center
Siyuan Zheng: Greehey Children’s Cancer Research Institute
Yidong Chen: Greehey Children’s Cancer Research Institute
Gang Huang: UT Health San Antonio
Neelam Mukherjee: UT Health
Robert Hromas: UT Health
Patrick Sung: Greehey Children’s Cancer Research Institute
Virginia Kaklamani: UT Health
Ratna Vadlamudi: UT Health San Antonio
Nu Zhang: Audie L. Murphy Division, South Texas Veterans Health Care System
Manjeet K. Rao: Greehey Children’s Cancer Research Institute

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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 and DNMT1, and lower levels of STING and ULBP1, have worse survival and are less responsive to immunotherapy. Collectively, our findings provide key insight into how a tumor-intrinsic transcription factor epigenetically shapes the tumor immune microenvironment, with strong implications for refining existing and designing new cancer immunotherapies.

Date: 2025
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DOI: 10.1038/s41467-025-59186-3

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