Targeting SMARCA2-Dependent SOX2 Condensates Suppresses Lung Adenocarcinoma Progression

SRY-box transcription factor 2 (SOX2), a prominent transcription factor, is frequently dysregulated in Lung adenocarcinoma (LUAD) the most common histological subtype of lung cancer. However, its precise role in tumorigenesis is unclear, and its therapeutic targeting poses significant challenges. Here, we demonstrate that suppressing SOX2 expression in adenocarcinoma cells attenuates cell proliferation, migration, invasion, and clonogenicity. Mechanistically, dysregulated SOX2 undergoes liquid-liquid phase separation (LLPS) to form condensates that recruit histone acetyltransferases, thereby facilitating the transcription of pro‑tumorigenic genes. Proteomic analysis of isolated SOX2 condensates identified SWI/SNF related BAF chromatin remodeling complex subunit ATPase 2 (SMARCA2), a subunit of the SWI/SNF chromatin remodeling complex, as a key component. The bromodomain of SMARCA2 is essential for its interaction with SOX2; loss of this domain markedly reduces SOX2 condensate formation in LUAD cells resulting the reversion of malignant phenotype. As a practical therapeutic strategy, degrading SMARCA2 via pharmacological means achieves potent tumor suppression in models both in vitro and in vivo. Taken together, our findings reveal that SOX2 drives tumorigenic properties in LUAD through LLPS, and that targeting SMARCA2 to disrupt its condensate integrity represents a promising therapeutic strategy.