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AXL Kinase Inhibition Promotes Cytosolic DNA Sensor cGAS Activity and Sensitizes Poorly Immunogenic Tumors to

Sushil Dhakal1, Muntequa I Siraji1, Sturla M Grøndal1

  • 1Department of Biomedicine, Center for Cancer Biomarkers (CCBIO), University of Bergen, Bergen, Norway.

Molecular Cancer Therapeutics
|November 20, 2025
PubMed

Insights

AXL protein suppresses anti-tumor immunity by inhibiting the cGAS pathway. Targeting AXL with chemo-immunotherapy enhances immune responses and treats resistant tumors.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • AXL receptor tyrosine kinase is a negative regulator of type I interferon (IFN) responses in viral infections.
  • In cancer, AXL promotes tumor progression, metastasis, immune evasion, and therapy resistance.
  • The role of AXL in regulating tumor cell-intrinsic IFN responses is not well understood.

Purpose of the Study:

  • To investigate the role of AXL in regulating intrinsic IFN responses within tumor cells.
  • To explore the therapeutic potential of AXL inhibition in combination with chemo-immunotherapy for refractory tumors.

Main Methods:

  • Investigated AXL's mechanism of action on cytosolic DNA sensing pathways.
  • Utilized AXL inhibition in preclinical models of poorly immunogenic and immunotherapy-refractory tumors.
  • Assessed anti-tumor effects, IFN activation, immune cell infiltration, and cGAMP levels.

Main Results:

  • AXL suppresses tumor-intrinsic IFN responses by inhibiting the cGAS sensor through an AKT-dependent pathway.
  • AXL inhibition, combined with chemo-immunotherapy, showed significant anti-tumor activity in resistant tumors.
  • AXL inhibition led to increased cGAMP, IFN activation, and enhanced T cell and NK cell infiltration.

Conclusions:

  • AXL plays a novel role in suppressing tumor-intrinsic IFN responses.
  • Targeting AXL is a promising strategy to overcome chemo-immunotherapy resistance in tumors.
  • AXL inhibition can re-sensitize tumors to immunotherapy by restoring IFN signaling and immune cell infiltration.

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