Tumor cell-intrinsic TET3 restrains type I interferon signaling and anti-tumor immunity.

The ten-eleven translocation (TET) family genes, which encode 5-methylcytosine (5mC) dioxygenases, play a "double-edged sword" role in tumor initiation and progression. However, the functional role and molecular mechanism of tumor cell-intrinsic TET3 in anti-tumor immunity remain incompletely understood. Here, we uncover that TET3 mRNA expression was aberrantly elevated in multiple cancer types and correlated with poor overall survival. Transcriptomic analysis reveals that TET3 depletion upregulated the expression of innate immune response genes, including numerous interferon-stimulated genes (ISGs), in cancer cells. The expression levels of dsRNA sensors (i.e., MDA5 and RIG-I) were increased in TET3 KO or KD cells, while the biogenesis of endogenous dsRNA was not affected. Mechanistically, TET3 regulates type I interferon signaling by inhibiting STAT1 activation. Importantly, depletion of TET3 in B16F10 melanoma cells significantly curbed the synergistic tumor growth, accompanied by increased tumor-infiltrating CD4+ T cells, CD8+ T cells, and dendritic cells. Notably, analysis of the TCGA dataset also shows that TET3 expression levels were negatively correlated with tumor-infiltrating cytotoxic CD8+ T cells and MHC-I expression across multiple cancer types. Taken together, our findings identify TET3 as a new negative regulator of the type I interferon signaling in cancer cells. We envisage that targeting the tumor cell-intrinsic TET3 could reduce tumor immune evasion and promote anti-tumor immunity.