Novel CRISPR-Cas9 BAP1 knockout pre-clinical tumor model recapitulates human melanoma tumorigenesis and immune evolution.

BAP1-deficient melanocytic tumors exhibit strong immunosuppressive features and poor prognosis. Currently, no immune-competent preclinical models exist to study their tumor-immune interactions or test new immunotherapies. This limitation hinders progress in understanding how BAP1 loss drives tumor aggressiveness and immune evasion. To address this, we generate a syngeneic BAP1 knockout melanocyte tumor line using CRISPR-Cas9. We then evaluate its functional and immunological impact in immune-competent mice, including its ability to recapitulate metabolic and immunosuppressive features of human BAP1-deficient melanomas. The selected knockout clone exhibits hallmarks of aggressive skin and intraocular melanomas, including epithelioid morphology, in vivo tumorigenic potential, rapid growth, and key immunosuppressive features, mirroring those observed in human BAP1-deficient melanomas. Cross-species single-cell transcriptome analysis demonstrates strong molecular overlap between BAP1 knockout mouse tumors and high-risk (class 2) human uveal melanomas, highlighting shared pathways in lipid metabolism, transmembrane receptor signaling, and immune modulation. Gene Set Enrichment Analysis confirms that lipid metabolic reprogramming, previously described in human tumors, is also a key feature of our model, validating its ability to recapitulate human disease biology. This study introduces a syngeneic preclinical model that mimics the immunosuppressive landscape of BAP1-deficient melanocytic tumors, enabling the development and optimization of new combination immunotherapies.