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

  • Sci Adv. 2026 Jun 12;12(24):eaef1962. doi: 10.1126/sciadv.aef1962.
Jin-Fen Xiao  1 ,  Emily Y Ko  1 ,  Ashley Smith  1 ,  Roberta Piras  2 ,  Annaliese Fowler  1 ,  Kristin Ishaya  3 ,  Longqiang Wang  1 ,  Bin Wang  1 ,  Adriana Paulucci-Holthauzen  1 ,  Sharon M Landers  4 ,  Angela D Bhalla  4 ,  Keila E Torres  4 ,  Diana Shamsutdinova  5 ,  Khalida M Wani  5 ,  Alexander J Lazar  5 ,  Emily Z Keung  4 ,  Neeta Somaiah  6 ,  Elise F Nassif Haddad  6 ,  Jlenia Guarnerio  1
Affiliations
  • 1. Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 2. Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 3. Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 4. Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5. Department of Anatomical Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 6. Department of Sarcoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
PMID: 42284392 DOI: 10.1126/sciadv.aef1962
Abstract

Soft tissue sarcomas are aggressive malignancies with limited responses to immunotherapy. Strategies that induce viral mimicry and type I interferon (IFN-I) signaling may enhance tumor immunogenicity but remain poorly explored in sarcoma. Here, we show that the CDK4/6 inhibitor abemaciclib triggers viral mimicry and robust IFN-I responses in sarcoma cells, leading to tumor growth suppression and remodeling of the tumor microenvironment toward an immune-permissive state. However, sarcoma cells activate resistance mechanisms that limit IFN-induced stress. We identify lysophosphatidic acid receptor 4 (LPAR4) as a key mediator of this adaptation. LPAR4 dampens IFN signaling, reduces oxidative stress, and promotes tumor cell survival under therapeutic pressure. Genetic silencing of LPAR4 enhances IFN responses, increases Reactive Oxygen Species, and sensitizes sarcoma cells to Apoptosis, resulting in delayed tumor growth. These findings identify LPAR4 as a central regulator of IFN-driven stress adaptation and a potential therapeutic target to enhance viral mimicry-based strategies in sarcoma.

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