Synergistic therapy for pancreatic cancer by deactivating cancer-associated fibroblasts and driving T-cell migration into tumor microenvironment using nanochaperone delivery system

Synergistic therapy for pancreatic cancer by deactivating cancer-associated fibroblasts and driving T-cell migration into tumor microenvironment using nanochaperone delivery system

The success of immunotherapy in pancreatic ductal adenocarcinoma (PDAC) is greatly limited by the scarcity of cytotoxic T lymphocytes (CTLs) in tumor microenvironment, which is mainly due to the physical barrier formed by a dense extracellular matrix (ECM). Here we reported a potent strategy to rect...

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Bibliographic Details
Main Authors: Jiajing Chen, Feihe Ma, Yujie Chen, Mengchen Xu, Yongxin Zhang, Shuyu Wang, Hongyun Liu, Linlin Xu, Yang Liu, Rujiang Ma, Jinpu Yu, Linqi Shi
Format: Article
Language:English
Published: KeAi Communications Co., Ltd. 2025-10-01
Series:Bioactive Materials
Subjects:
Pancreatic cancer
Chemokines
Cancer-associated fibroblasts
T cell migration
Nanochaperone
Online Access:http://www.sciencedirect.com/science/article/pii/S2452199X25002397
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Summary:The success of immunotherapy in pancreatic ductal adenocarcinoma (PDAC) is greatly limited by the scarcity of cytotoxic T lymphocytes (CTLs) in tumor microenvironment, which is mainly due to the physical barrier formed by a dense extracellular matrix (ECM). Here we reported a potent strategy to rectify the CTLs infiltration in PDAC by synergistically deactivating cancer-associated fibroblasts (CAFs) and driving T-Cell migration into tumor microenvironment. This combination therapy is achieved by co-delivery of vitamin D receptor ligand (calcipotriol, Cal) and chemokine (CXCL9) using nanochaperone (nChap) delivery platform. We demonstrate that Cal reverses the activated CAFs to quiescence for resulting in a loosened ECM, while the CXCL9 gradient increases the recruitment signal of CD8+ T cells, synergistically enhancing the intratumoral infiltration of CD8+ T cells. Noteworthily, this system (Cal@nChap-CXCL9) promotes both the penetration of immunotherapeutic (anti-PD-1) and chemotherapeutic (gemcitabine), significantly enhancing the efficacy of chemo-immunotherapy for advanced large Panc02 tumors. This study provides a promising strategy for enhanced PDAC immunotherapy.
ISSN:2452-199X

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