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Updated: May 26, 2026

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Published on: March 15, 2024

Mitochondrial Carrier SLC25A13 Drives Ferroptosis Resistance and Immune Evasion via a STAT3-IFI6 Circuit in Breast

Yingze Zhu1, Yuhan Tang1, Yingcui Chen1

  • 1The Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, P. R. China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|May 25, 2026
PubMed

Insights

Triple-negative breast cancer (TNBC) is resistant to immunotherapy. Researchers found that targeting the SLC25A13 protein can enhance ferroptosis, boost anti-tumor immunity, and improve immunotherapy effectiveness in TNBC models.

Area of Science:

  • Immunometabolism
  • Cancer Biology
  • Molecular Oncology

Background:

  • Triple-negative breast cancer (TNBC) exhibits poor response to immunotherapy.
  • The role of ferroptosis in modulating antitumor immunity in TNBC is not well understood.
  • Identifying novel immunometabolic targets is crucial for enhancing TNBC treatment.

Purpose of the Study:

  • To identify key immunometabolic drivers in TNBC.
  • To elucidate the mechanism by which these drivers affect ferroptosis and T-cell immunity.
  • To explore therapeutic strategies targeting identified pathways for improved TNBC immunotherapy.

Main Methods:

  • Identified SLC25A13 as a key immunometabolic driver in TNBC.
  • Investigated the functional role of SLC25A13 in tumor growth, metastasis, and immune evasion.
  • Elucidated the molecular mechanism involving SLC25A13, STAT3, and IFI6.
  • Screened for small-molecule inhibitors targeting SLC25A13.
  • Evaluated the efficacy of a novel SLC25A13 degrader in combination with anti-PD-1 therapy in TNBC models.

Main Results:

  • SLC25A13 is upregulated in TNBC, correlating with poor prognosis and reduced CD8+ T-cell infiltration.
  • SLC25A13 promotes tumor progression, suppresses ferroptosis, and impairs CD8+ T-cell cytotoxicity by enhancing oxidative phosphorylation and restraining ROS.
  • The SLC25A13-STAT3-IFI6 axis confers ferroptosis resistance and immune evasion.
  • A novel SLC25A13 degrader (HY-QS02682823) enhanced ferroptosis, restored CD8+ T-cell function, and improved anti-PD-1 therapy efficacy.

Conclusions:

  • The SLC25A13-STAT3-IFI6 axis is a critical regulator of ferroptosis resistance and immune evasion in TNBC.
  • Targeting SLC25A13 represents a promising strategy to enhance antitumor immunity and immunotherapy efficacy in TNBC.
  • Further investigation into immunometabolic pathways offers new avenues for TNBC treatment development.

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