UHRF1 as an epigenetic driver of tumorigenicity and immune evasion in triple negative breast cancer

Ubiquitin-like with PHD and RING Finger Domains 1 (UHRF1) is a multidomain epigenetic regulator essential for the maintenance of DNA methylation and repressive histone marks during cell division. As a downstream effector of the RB/E2F pathway, frequently deregulated in cancer, UHRF1 is aberrantly overexpressed in several malignancies, including triple-negative breast cancer (TNBC). Clinical datasets reveal that high UHRF1expression correlates with poor overall survival in TNBC, underscoring its clinical relevance.Using CRISPR/Cas9-mediated gene editing, we demonstrate that UHRF1 loss significantly impairs TNBC cell tumorigenicity. UHRF1-deficient TNBC cells exhibited reduced clonogenicity, migration, and invasion in vitro. In orthotopic xenograft models, tumors with low UHRF1 expression displayed significantly reduced growth and metastatic potential compared to controls. Transcriptomic profiling revealed that UHRF1 loss led to widespread depression of immune-related genes, suggesting that UHRF1 orchestrates an epigenetically repressed, immune-evasive state. To validate these findings in an immunocompetent context, Uhrf1 knockout (KO) TNBC cell lines were generated from mouse 4T1 cells.Consistent with human models, Uhrf1 KO cells displayed reduced tumorigenic potential and formed significantly smaller tumors in Balb/cJ mice. Importantly, Uhrf1 KO tumors showed increased infiltration of activated cytotoxic T cells (CD8+ CD44hi) and plasmacytoid dendritic cells (pDCs), alongside a higher cytotoxic-to-regulatory T cell ration, indicating an enhanced anti-tumor immune landscape following loss of UHRF1-mediated repression.Together, these results establish UHRF1 as a master epigenetic regulator linking the RB/E2F axis to tumor progression and immune modulation in TNBC. Targeting UHRF1-dependent chromatin regulation may represent a promising strategy to simultaneously suppress tumor growth and overcome immune evasion in aggressive breast cancers.