SOX2 is a dispensable modulator of NUT carcinoma oncogenesis in mouse

NUT carcinoma (NC) is a highly aggressive malignancy driven by BRD4::NUTM1 and other NUTM1 fusion oncogenes. BRD4::NUTM1 aberrantly activates transcription factors (TFs) linked to basal progenitor identity, producing poorly differentiated squamous phenotypes. Among these TFs, SOX2 has been proposed as a critical oncogenic driver, but its functional requirement in NC has not been tested 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. We found that Sox2 is dispensable for NC initiation and progression, with tumors retaining characteristic histology and expression of key drivers including BRD4::NUTM1 , MYC , and TP63 . Transcriptomic profiling revealed only modest changes in Sox2 -deficient tumors, mainly affecting metabolic and biosynthetic pathways, without disrupting core oncogenic programs. These findings challenge the assumption that SOX2 is universally required in NC and suggest that SOX2-targeted therapies may have limited utility, refining the framework for therapeutic prioritization.