Disrupting SOX2 self-association and condensate formation to overcome chemotherapeutic drug resistance in lung squamous cell carcinoma

  • Signal Transduct Target Ther. 2026 May 13;11(1):183. doi: 10.1038/s41392-026-02696-3.
Juehan Wang  1  2  3  4 ,  Yulin Wen  1  3 ,  Sainan Huang  1  3 ,  Yanjiang Liu  1  2 ,  Xiaotao Dong  5 ,  Hongmo Liu  6  7 ,  Zhihua Guo  8 ,  Jin Li  1 ,  Chengzhi Zhou  9 ,  Hua Wang  10 ,  Lingling Zhang  10 ,  Zhoufeng Wang  6  7 ,  Weimin Li  6  7 ,  Hongjie Yao  11  12  13
Affiliations
  • 1. State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China.
  • 2. Department of Basic Research, Guangzhou National Laboratory, Guangzhou, China.
  • 3. Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
  • 4. University of Chinese Academy of Sciences, Beijing, China.
  • 5. School of Basic Medical Sciences, Henan University, Kaifeng, China.
  • 6. Department of Pulmonary and Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
  • 7. State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, China.
  • 8. Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, China.
  • 9. The First Affiliated Hospital of Guangzhou Medical University, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China.
  • 10. Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China.
  • 11. State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China. [email protected].
  • 12. Department of Basic Research, Guangzhou National Laboratory, Guangzhou, China. [email protected].
  • 13. University of Chinese Academy of Sciences, Beijing, China. [email protected].
PMID: 42143069 DOI: 10.1038/s41392-026-02696-3
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, Hx1R8, 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.

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