Targeting LPAR4 overcomes stress adaptation to CDK4/6 inhibition in soft tissue sarcoma [CITEseq]

CDK4/6 inhibitors are under active clinical evaluation in sarcoma, yet the mechanisms governing sensitivity and resistance remain unclear. We show that the CDK4/6 inhibitor abemaciclib not only suppresses tumor cell proliferation but also induces robust type I interferon signaling driven by dsRNA accumulation, which is essential for its anti-tumor activity. Abemaciclib reshapes the sarcoma immune microenvironment by increasing T cell infiltration and enhancing intratumoral interferon-producing monocytes. Integrated transcriptomic and proteomic analyses identified Lysophosphatidic Acid Receptor 4 (LPAR4) as an adaptive stress-response factor upregulated in tumor cells upon treatment and associated with poor patient prognosis. Functionally, LPAR4 mitigates interferon-induced mitochondrial stress, limiting reactive oxygen species accumulation and apoptosis, while its silencing exacerbates mitochondrial dysfunction and promotes tumor cell death. In vivo, LPAR4 loss synergizes with abemaciclib to inhibit tumor growth and prolong survival. These findings establish LPAR4 as a key regulator of stress adaptation and a promising target to potentiate CDK4/6-based therapies.