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

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

doi:10.1016/j.bioactmat.2025.06.010

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

Bioact Mater. 2025 Jun 11:52:287-299. doi: 10.1016/j.bioactmat.2025.06.010. eCollection 2025 Oct.

Authors

Jiajing Chen¹, Feihe Ma², Yujie Chen², Mengchen Xu², Yongxin Zhang², Shuyu Wang³, Hongyun Liu², Linlin Xu², Yang Liu², Rujiang Ma², Jinpu Yu³, Linqi Shi^{3

2}

Affiliations

¹ Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin Institute of Hepatobiliary Disease, The Third Central Hospital of Tianjin, Tianjin, 300170, China.
² 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.
³ Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.

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.

Keywords: Cancer-associated fibroblasts; Chemokines; Nanochaperone; Pancreatic cancer; T cell migration.