Targeting oncogenic SOX2 condensates suppresses squamous cell carcinoma progression.

Squamous cell carcinomas (SCCs) comprise a group of lethal malignancies, yet developing SCC-specific therapies remains challenging, largely due to a lack of druggable targets. We identify SOX2 condensation as a shared cancer hallmark across esophageal, head and neck, and lung SCCs. Within SOX2, the activation domain 1 (AD1) acts as the condensate-promoting region via its aromatic and hydrophobic residues. Site-specific mutagenesis, orthotopic mouse models, and multi-omics sequencing demonstrate that SOX2 condensates upregulate oncogene expression by enhancing SOX2 chromatin occupancy, H3K27ac enrichment, and chromatin interactions at oncogenic loci such as FGFR2, thereby promoting SCC progression. An FDA-approved drug screen reveals that the proteasome inhibitor ixazomib disrupts SOX2 condensates in an HSP70-dependent manner. Upon ixazomib treatment, the substrate-binding domain of HSP70 blocks SOX2 AD1, selectively dissolving SOX2 condensates, downregulating oncogene expression, and suppressing condensate-positive SCC patient-derived xenografts. These findings highlight targeting SOX2 condensates with proteasome inhibitors as an SCC-specific, biomarker-guided therapeutic strategy.