Abstract

Chemotherapy remains a primary treatment for lung squamous cell carcinoma (LSCC), and its efficacy is limited due to drug resistance; however, the mechanisms involved in drug resistance are still unclear. In this study, we identify a significant correlation between SOX2 amplification and elevated mRNA expression in LSCC patients, establishing SOX2 as a key regulator of LSCC. Our data further demonstrate that SOX2 drives chemoresistance by forming biomolecular condensates via phase separation. SOX2 condensates function as protective compartments that physically sequester chemotherapeutic drugs, reducing availability to intracellular targets and cytotoxicity of these chemotherapeutic drugs. Exposure to chemotherapeutic stress further upregulates SOX2 expression and promotes its phase separation, thereby creating a vicious self-reinforcing cycle that amplifies chemoresistance. To overcome drug resistance induced by SOX2 condensation, we developed a cell-penetrating peptide, Hx1 R8 , that disrupts SOX2 self-association and condensate formation by specifically targeting the α-helix region of the HMG domain, while preserving its transcriptional activity. This cell-penetrating peptide could effectively reverse chemoresistance in LSCC, restore drug sensitivity, and exhibit a favorable safety profile. Taken together, our findings not only reveal the molecular mechanisms underlying chemotherapeutic drug-induced SOX2 overexpression and phase separation but also propose a promising peptide-based therapeutic strategy targeting SOX2 to overcome treatment failure in LSCC.