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.
Authors
- Jingjing Wei (ORCID: https://orcid.org/0000-0002-2197-8062)
- Hong‐Wen Liu (ORCID: https://orcid.org/0000-0001-8757-1620)
- Shanshan Shen (ORCID: https://orcid.org/0000-0003-3249-1564)
- Yuxiang Sun (ORCID: https://orcid.org/0009-0002-0915-6557)
- Xudong Zhu (ORCID: https://orcid.org/0000-0002-0873-6800)
- Yani Pan (ORCID: https://orcid.org/0000-0002-4755-9878)
- Ge Bai (ORCID: https://orcid.org/0000-0002-2878-1772)
- Yun Zhu (ORCID: https://orcid.org/0000-0002-1299-6509)
- Zhangding Wang (ORCID: https://orcid.org/0000-0002-3959-4542)
- Yue Zhou (ORCID: https://orcid.org/0000-0002-1335-5703)
- Lei Wang (ORCID: https://orcid.org/0000-0001-8172-5334)
- Yang Liu (ORCID: https://orcid.org/0000-0002-9442-700X)
- Lu Xu (ORCID: https://orcid.org/0009-0003-4772-9608)
- Xin Fu (ORCID: https://orcid.org/0000-0001-9726-9388)
- Qi Chen
- Lina Zhou (ORCID: https://orcid.org/0000-0003-0815-2458)
- Yu‐Guang Zhou (ORCID: https://orcid.org/0000-0001-5887-9781)
- Nannan Zhang
- Lishan Wang
- Lei Xu (ORCID: https://orcid.org/0000-0003-1280-6506)
Institutions
- Nanjing University of Chinese Medicine (CN)
- China Pharmaceutical University (CN)
- Nanjing Drum Tower Hospital (CN)
- Yangzhou University (CN)
Publication Details
- Journal
- Advanced Functional Materials
- Published
- 2025-06-06
- DOI
- https://doi.org/10.1002/adfm.202423217
- Citations
- 1
- Primary Topic
- Nanoplatforms for cancer theranostics
- Type
- article
- Field-Weighted Citation Impact
- 0.67
Funders
- National Natural Science Foundation of China
- Government of Jiangsu Province