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

Lu Liu1, Wenxuan Zhao1, Tianbao Shang1

  • 1Longevity and Aging Institute, Zhongshan Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.

Science China. Life Sciences
|May 11, 2026
PubMed

Insights

Ten-eleven translocation 3 (TET3) is elevated in cancers and suppresses anti-tumor immunity by inhibiting type I interferon signaling. Targeting TET3 boosts immune responses against tumors.

Area of Science:

  • * Molecular biology
  • * Immunology
  • * Cancer research

Background:

  • * Ten-eleven translocation (TET) family genes encode dioxygenases involved in DNA demethylation.
  • * TET family genes have a complex role in cancer initiation and progression.
  • * The specific function of TET3 within cancer cells regarding anti-tumor immunity is not fully understood.

Purpose of the Study:

  • * To investigate the role and molecular mechanism of tumor cell-intrinsic TET3 in anti-tumor immunity.
  • * To determine the impact of TET3 on type I interferon signaling and immune cell infiltration in tumors.

Main Methods:

  • * Analysis of TET3 mRNA expression in cancer patient data (TCGA).
  • * CRISPR/Cas9 knockout (KO) and knockdown (KD) of TET3 in cancer cell lines.
  • * Transcriptomic analysis (RNA-seq) to assess gene expression changes.
  • * Assessment of immune cell infiltration in tumors using flow cytometry and IHC.

Main Results:

  • * TET3 mRNA is upregulated in multiple cancer types and associated with poor survival.
  • * TET3 depletion enhances innate immune gene expression, including interferon-stimulated genes (ISGs).
  • * TET3 inhibition increases dsRNA sensor expression (MDA5, RIG-I) and suppresses type I interferon signaling via STAT1 inhibition.
  • * TET3 deficiency reduces tumor growth and increases CD4+, CD8+ T cell, and dendritic cell infiltration.
  • * High TET3 expression correlates with reduced CD8+ T cell infiltration and MHC-I expression in human cancers.

Conclusions:

  • * TET3 acts as a novel negative regulator of type I interferon signaling within cancer cells.
  • * Targeting tumor cell-intrinsic TET3 can potentially overcome immune evasion and enhance anti-tumor immunity.
Keywords:
STAT1TET3anti-tumor immunitytype I interferon signaling

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