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LPAR4 mediates resistance to interferon-induced stress in soft tissue sarcoma

Jin-Fen Xiao1, Emily Y Ko1, Ashley Smith1

  • 1Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Science Advances
|June 12, 2026
PubMed

Insights

The CDK4/6 inhibitor abemaciclib triggers viral mimicry and interferon responses in soft tissue sarcoma. Targeting LPAR4 enhances these effects, offering a new strategy to improve immunotherapy for sarcoma.

Area of Science:

  • Oncology
  • Immunology
  • Pharmacology

Background:

  • Soft tissue sarcomas are aggressive cancers with poor responses to immunotherapy.
  • Viral mimicry and type I interferon (IFN-I) signaling can enhance anti-tumor immunity but are understudied in sarcoma.

Purpose of the Study:

  • To investigate if CDK4/6 inhibitors can induce viral mimicry and IFN-I responses in sarcoma.
  • To identify resistance mechanisms to IFN-I signaling in sarcoma.
  • To explore LPAR4 as a therapeutic target to enhance immunotherapy in sarcoma.

Main Methods:

  • Treatment of sarcoma cells with abemaciclib.
  • Analysis of IFN-I signaling and viral mimicry.
  • Genetic silencing of LPAR4.
  • Assessment of tumor growth and microenvironment changes in vivo.

Main Results:

  • Abemaciclib induced viral mimicry and IFN-I responses in sarcoma cells, suppressing tumor growth and promoting an immune-permissive microenvironment.
  • Sarcoma cells developed resistance to IFN-I-induced stress via LPAR4.
  • LPAR4 dampened IFN signaling and oxidative stress, promoting cell survival.
  • Silencing LPAR4 enhanced IFN responses, increased reactive oxygen species, and sensitized sarcoma cells to apoptosis, delaying tumor growth.

Conclusions:

  • Abemaciclib triggers beneficial anti-tumor immune responses in sarcoma by inducing viral mimicry and IFN-I signaling.
  • LPAR4 is a key mediator of resistance to IFN-I-driven stress in sarcoma.
  • Targeting LPAR4 may enhance the efficacy of viral mimicry-based immunotherapies for soft tissue sarcomas.

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