Reprogramming tumor microenvironment by CAF-targeted sonodynamic therapy combined with chemotherapy

Abstract Pancreatic cancer is one of the most invasive malignant tumors, with poor drug efficacy. Sonodynamic therapy (SDT) has emerged as a promising tumor treatment method. However, cancer-associated fibroblasts (CAFs) limit the efficacy of SDT and contribute to poor therapeutic response. Therefore, developing SDT strategies targeting CAFs in combination with chemotherapy to reshape the drug-resistant tumor microenvironment is critical for enhancing drug therapeutic outcomes in pancreatic cancer. Here, we constructed a CAF-targeted SDT-chemotherapy system named FnBPA5-IR-CF3@Dox, which can actively accumulate in CAFs and achieve effective SDT effect. Upon ultrasound irritation, FnBPA5-IR-CF3@Dox eliminates CAFs at pancreatic tumor sites, resulting in reduction of tumor interstitial fluid pressure, downregulation of interstitial fibrosis, enhanced CD8 + T cell infiltration into tumors, and improved drug penetration to tumor sites. This CAFs-targeted SDT combined with chemotherapy strategy significantly enhances chemotherapy efficacy and inhibits pancreatic cancer progression. It suggests that CAFs-targeted SDT combined with chemotherapy represents a promising approach for tumor microenvironment reprogramming in clinical pancreatic cancer treatment.