SOX2 is a dispensable modulator of NUT carcinoma oncogenesis in mice.

NUT carcinoma (NC) is an aggressive malignancy driven by BRD4::NUTM1 and other NUTM1 fusion oncogenes. BRD4::NUTM1 aberrantly activates transcription factors (TFs) associated with basal progenitor cells of stratified epithelium, resulting in a poorly differentiated squamous cell carcinoma (SCC) phenotypes. Among these TFs, SOX2 has been proposed as a critical driver. However, its role in NC initiation and progression has not been investigated in vivo. Using a genetically engineered mouse model that faithfully recapitulates human NC, we performed lineage-specific conditional deletion of Sox2 in both squamous and non-squamous tissues during NC oncogenesis. We found that SOX2 is dispensable for NC initiation and progression, and that tumors lacking SOX2 retain characteristic histological features and expression of key oncogenic drivers, including BRD4::NUTM1, MYC, and TP63. Bulk RNA sequencing revealed only modest transcriptional changes in SOX2-deficient tumors, primarily affecting metabolic and biosynthetic pathways, without disrupting core oncogenic programs. These findings challenge the assumption that SOX2 is universally required for NC oncogenesis and highlight the autonomy of BRD4::NUTM1 in establishing and maintaining the NC phenotype. Our results suggest that SOX2 is dispensable for NC and redirect therapeutic focus toward BRD4::NUTM1 and its chromatin remodeling dependencies.