Related Experiment Video

Updated: Apr 21, 2026

The Drosophila Imaginal Disc Tumor Model: Visualization and Quantification of Gene Expression and Tumor Invasiveness Using Genetic Mosaics
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The Drosophila Imaginal Disc Tumor Model: Visualization and Quantification of Gene Expression and Tumor Invasiveness Using Genetic Mosaics

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Mutant KRAS Suppresses DNA Sensing by Remodeling Membrane Tension to Clear Extracellular Tumor DNA

Di Cao1, Weiyi Zhou2, Zhixiong Li3

  • 1Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.

Cancer Research
|April 19, 2026
PubMed

Insights

Oncogenic KRAS regulates extracellular tumor DNA (tDNA) levels by inducing CD9, which promotes tDNA clearance and immune evasion. Blocking CD9 restores tDNA and enhances cancer immunotherapy efficacy.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Immunology

Background:

  • Extracellular tumor-derived DNA (tDNA) is a key biomarker for cancer management.
  • Understanding tDNA regulation mechanisms is crucial for improving cancer biomarkers and therapies.

Purpose of the Study:

  • To identify regulators of extracellular tDNA abundance.
  • To elucidate the role of oncogenic KRAS in tDNA regulation and immune evasion.
  • To explore therapeutic strategies targeting the identified pathway.

Main Methods:

  • Investigated the role of oncogenic KRAS in regulating tDNA levels.
  • Utilized molecular biology techniques to study the KRAS-CD9-FXR1 pathway.
  • Assessed the impact of CD9 modulation on tDNA clearance and immune cell function.
  • Evaluated the therapeutic potential of CD9 blockade in combination with PD-1 inhibitors in cancer models.

Main Results:

  • Oncogenic KRAS was identified as a critical regulator of tDNA levels.
  • Mutant KRAS promotes tDNA clearance via CD9 induction, FXR1 recruitment, and actin remodeling, leading to reduced plasma membrane tension and enhanced endocytic uptake.
  • Reduced tDNA levels dampen ZBP1-dependent DNA sensing in tumor-associated macrophages (TAMs), promoting an immunosuppressive state.
  • CD9 blockade restored extracellular tDNA and DNA sensing, reprogrammed TAMs, and synergized with PD-1 blockade in KRAS-mutant cancer models.

Conclusions:

  • A novel KRAS-CD9-FXR1 pathway links membrane mechanics to extracellular DNA clearance and immune evasion.
  • Targeting CD9 represents a promising strategy to enhance the efficacy of immune checkpoint blockade therapy for KRAS-mutant cancers.

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