HPV Enhances HNSCC Chemosensitization by Inhibiting SERPINB3 Expression to Disrupt the Fanconi Anemia Pathway

Head and neck squamous cell carcinoma (HNSCC) is the most common malignant tumor of the head and neck, and the prognosis of patients is poor due to chemotherapeutic resistance. Interestingly, patients with HNSCC induced by human papillomavirus (HPV) infection are more sensitive to chemotherapy and display a better prognosis than HPV‐negative patients. The biological relevance of HPV infection and the mechanism underlying chemosensitivity to cisplatin remain unknown. Herein, SERPINB3 is identified as an important target for regulation of cisplatin sensitivity by HPV‐E6/E7 in HNSCC. Downregulation of SERPINB3 inhibits cisplatin‐induced DNA damage repair and enhances the cytotoxicity of cisplatin. In detail, decreasing SERPINB3 expression reduces the USP1‐mediated deubiquitination of FANCD2–FANCI in the Fanconi anemia pathway, thereby interfering with cisplatin‐induced DNA interstrand crosslinks repair and further contributing to HNSCC cell apoptosis. To translate this finding, pH‐responsive nanoparticles are used to deliver SERPINB3 small interfering RNA in combination with cisplatin, and this treatment successfully reverses cisplatin chemotherapeutic resistance in a patient‐derived xenograft model from HPV‐negative HNSCC. Taken together, these findings suggest that targeting SERPINB3 based on HPV‐positive HNSCC is a potential strategy to overcome cisplatin resistance in HPV‐negative HNSCC and improves the prognosis of this disease.