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

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.