Enhancing PD-1 Inhibitor Efficacy in Cholangiocarcinoma by Reprogramming Tumor-Associated Neutrophils With CAF-Derived Extracellular Vesicles Loaded with Ruxolitinib

Abstract

Tumor-associated neutrophils (TANs), particularly the N2 phenotype, contribute to T cell exhaustion in cholangiocarcinoma (CCA), leading to low response rates to PD-1 inhibitor therapy. To address this issue, cancer-associated fibroblast (CAF)-derived extracellular vesicles loaded with ruxolitinib (CEVs@Ru) are developed to selectively target and reprogram N2 TANs, thereby modulating the immunosuppressive tumor microenvironment (TME). The combination of CEVs@Ru with anti-PD-1 antibody therapy significantly enhanced antitumor efficacy, reducing tumor weight by 89.86% and normalizing liver weight, without significant adverse effects. This approach improved the local concentration of ruxolitinib, increased CD8+ T cell infiltration, and reduced regulatory T cells, indicating a remodeled TME conducive to effective antitumor immunity. The findings provide a promising strategy for enhancing PD-1 inhibitor efficacy and improving patient outcomes in CCA and potentially other solid tumors.