Chen Jiajing, Ma Feihe, Chen Yujie, Xu Mengchen, Zhang Yongxin, Wang Shuyu, Liu Hongyun, Xu Linlin, Liu Yang, Ma Rujiang, Yu Jinpu, Shi Linqi
Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin Institute of Hepatobiliary Disease, The Third Central Hospital of Tianjin, Tianjin, 300170, China.
Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, Tianjin Key Laboratory of Functional Polymer Materials, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, 300071, China.
Bioact Mater. 2025 Jun 11;52:287-299. doi: 10.1016/j.bioactmat.2025.06.010. eCollection 2025 Oct.
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.
免疫疗法在胰腺导管腺癌（PDAC）中的成功受到肿瘤微环境中细胞毒性T淋巴细胞（CTL）稀缺的极大限制，这主要是由于致密的细胞外基质（ECM）形成的物理屏障所致。在此，我们报告了一种有效的策略，通过协同使癌症相关成纤维细胞（CAF）失活并驱动T细胞迁移到肿瘤微环境中来纠正PDAC中CTL的浸润。这种联合疗法是通过使用纳米伴侣（nChap）递送平台共同递送维生素D受体配体（骨化三醇，Cal）和趋化因子（CXCL9）来实现的。我们证明，Cal使活化的CAF恢复到静止状态，从而导致ECM松弛，而CXCL9梯度增加了CD8 T细胞的募集信号，协同增强了CD8 T细胞在肿瘤内的浸润。值得注意的是，该系统（Cal@nChap-CXCL9）促进了免疫治疗药物（抗PD-1）和化疗药物（吉西他滨）的渗透，显著提高了晚期大型Panc02肿瘤的化学免疫治疗效果。这项研究为增强PDAC免疫治疗提供了一种有前景的策略。
