CIC::DUX4 sarcoma (CDS) is an exceptionally aggressive cancer characterized by very few available treatment choices. In this work, we describe a doxycycline-inducible CIC::DUX4 fusion mouse model and its derived cancer cell line, imChCDS, which accurately reproduces the molecular, histological, and immunological traits of human CDS. Our results establish that CIC::DUX4 expression alone is sufficient to initiate tumor development in susceptible soft connective tissue lineages. The imChCDS line preserves the transcriptional signature of its mesenchymal progenitor cells, readily forms metastatic tumors in hosts with functional immunity, and shows strong reliance on the P300/CBP transcriptional co-activators. Significantly, we reveal that CIC::DUX4/P300/CBP-driven repression of MHC class I (MHCI) constitutes a critical pathway for CDS immune evasion. Genetic disruption of CIC::DUX4 or pharmacological blockade of P300/CBP causes cell-cycle arrest in tumor cells, reinstates MHCI surface expression, and elicits potent anti-tumor immunity. This conversion changes the typically “cold” CDS tumor microenvironment into an inflamed “hot” state, ultimately promoting tumor regression. Collectively, these models provide a flexible and biologically faithful platform for exploring CDS disease mechanisms, dissecting immune escape mechanisms, and assessing novel therapies, particularly those targeting the CIC::DUX4/P300/CBP oncogenic pathway.
