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

IF 18 1区医学 Q1 ENGINEERING, BIOMEDICAL

Bioactive Materials Pub Date : 2025-06-11 DOI:10.1016/j.bioactmat.2025.06.010

Jiajing Chen , Feihe Ma , Yujie Chen , Mengchen Xu , Yongxin Zhang , Shuyu Wang , Hongyun Liu , Linlin Xu , Yang Liu , Rujiang Ma , Jinpu Yu , Linqi Shi

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引用次数: 0

Abstract

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.

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利用纳米伴侣传递系统使癌症相关成纤维细胞失活并驱动t细胞向肿瘤微环境迁移的胰腺癌协同治疗

胰腺导管腺癌（PDAC）免疫治疗的成功很大程度上受到肿瘤微环境中细胞毒性T淋巴细胞（ctl）缺乏的限制，这主要是由于致密的细胞外基质（ECM）形成的物理屏障。在这里，我们报道了一种有效的策略，通过协同失活癌症相关成纤维细胞（CAFs）和驱动t细胞向肿瘤微环境迁移来纠正PDAC中的ctl浸润。这种联合疗法是通过纳米伴侣（nChap）递送平台，将维生素D受体配体（钙三醇，Cal）和趋化因子（CXCL9）共同递送。我们证明Cal将活化的caf逆转为静止状态，导致ECM松弛，而CXCL9梯度增加CD8+ T细胞的募集信号，协同增强CD8+ T细胞的肿瘤内浸润。值得注意的是，该系统（Cal@nChap-CXCL9）促进了免疫治疗（抗pd -1）和化疗（吉西他滨）的渗透，显著提高了晚期大Panc02肿瘤的化疗免疫治疗效果。本研究为增强PDAC免疫治疗提供了一个有希望的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioactive Materials Biochemistry, Genetics and Molecular Biology-Biotechnology

CiteScore

28.00

自引率

6.30%

发文量

436

审稿时长

20 days

期刊介绍： Bioactive Materials is a peer-reviewed research publication that focuses on advancements in bioactive materials. The journal accepts research papers, reviews, and rapid communications in the field of next-generation biomaterials that interact with cells, tissues, and organs in various living organisms. The primary goal of Bioactive Materials is to promote the science and engineering of biomaterials that exhibit adaptiveness to the biological environment. These materials are specifically designed to stimulate or direct appropriate cell and tissue responses or regulate interactions with microorganisms. The journal covers a wide range of bioactive materials, including those that are engineered or designed in terms of their physical form (e.g. particulate, fiber), topology (e.g. porosity, surface roughness), or dimensions (ranging from macro to nano-scales). Contributions are sought from the following categories of bioactive materials: Bioactive metals and alloys Bioactive inorganics: ceramics, glasses, and carbon-based materials Bioactive polymers and gels Bioactive materials derived from natural sources Bioactive composites These materials find applications in human and veterinary medicine, such as implants, tissue engineering scaffolds, cell/drug/gene carriers, as well as imaging and sensing devices.