Depleting S100A4 in Cancer-Associated Fibroblasts Reverses Cisplatin Resistance in Esophageal Cancer

Esophageal cancer is a malignant tumor with high morbidity and mortality. Cisplatin is a first-line chemotherapeutic drug for the treatment of esophageal cancer. However, nearly half of the patients eventually develop acquired resistance, making cisplatin resistance a critical clinical challenge in treating esophageal cancer. Cancer-associated fibroblasts (CAFs) play a critical role in cisplatin resistance of esophageal cancer. We found that primary CAFs isolated from cisplatin-resistant esophageal cancer patients exhibited significantly elevated S100A4 protein levels and enhanced resistance to cisplatin. Thus, the high expression of S100A4 in CAFs is suggested to be closely linked to cisplatin resistance in clinical esophageal cancer. Herein, we designed a CREKA-Lipid@Fe-siS100A4 (C-L@F-siA4) system that can efficiently target and eliminate the S100A4 gene within CAFs. In vitro and in vivo experiments demonstrated the ability of C-L@F-siA4 to reverse the resistance and restore the effectiveness of cisplatin in treatment of esophageal cancer. This study provides a target for treating esophageal cancer with acquired cisplatin resistance and offers a strategy as an adjuvant method for chemotherapy of esophageal cancer.