2. Academic Validation
  3. A thermosensitive hydrogel with synergistic stromal targeting and antitumor immunity modulation for pancreatic cancer immunotherapy

A thermosensitive hydrogel with synergistic stromal targeting and antitumor immunity modulation for pancreatic cancer immunotherapy

  • Mater Today Bio. 2025 May 20:32:101882. doi: 10.1016/j.mtbio.2025.101882.
Guozhi Zhao 1,  Fan Guo 1,  Wenhui Yan 1,  Ying Qu 2,  Chongzheng Yan 3,  Huaiyou Lv 4,  Genju Li 1,  Jianxiong Zhao 5 6,  Hanmiao Xie 7,  Yizhe Li 1,  Tingting Tian 1,  Zhongxi Zhao 1 8
Affiliations

Affiliations

  • 1 Department of Pharmaceutics, Key Laboratory of Chemical Biology of Ministry of Education, State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Cheelloo College of Medicine, Shandong University, Jinan, Shandong Province, 250012, China.
  • 2 Department of Pharmacy, The Second Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, 247 Beiyuan Street, Jinan, Shandong Province, 250012, China.
  • 3 Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, Shandong University, Jinan, Shandong Province, 250100, China.
  • 4 Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong Province, 264003, China.
  • 5 Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, China.
  • 6 NMPA Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Cultural West Road, Jinan, Shandong Province, 250012, China.
  • 7 Shandong Research Center of Sports Science, Jinan, Shandong Province, 250102, China.
  • 8 National Enterprise Technology Center of Shandong DYNE Marine Biopharmaceutical Co., Ltd, Rongcheng, Shandong, 264300, China.
PMID: 40496724 DOI: 10.1016/j.mtbio.2025.101882
Abstract

Pancreatic Cancer is intrinsically characterized by an immunosuppressive microenvironment, in which the malignant extracellular matrix (ECM) creates a barrier that significantly impedes drug delivery, thereby undermining the overall anti-tumor immune responses. In this study, we present a novel thermosensitive hydrogel (SCC15+PLHCu@Gel) that co-deliver two types of nanoparticles loaded with the disulfiram derivative CPD12C15 (SCC15) and tumor-targeting Cu2+ (PLHCu) to overcome the degradation of CPD12C15 induced by Cu2+ within the same nano formulation. SCC15 effectively reduced α-SMA and Collagen I and increased lipid droplets in the cancer-associated fibroblasts (CAFs) by inhibiting the SMAD3 pathway, which was consistent with the ECM depletion achieved by using the in-vivo dosing of SCC15+PLHCu@Gel. In addition, the in-vivo treatment of SCC15+PLHCu@Gel significantly elevated pro-inflammatory cytokines IFN-γ, TNF-α and IL-12, indicating the remodeling of the suppressive tumor microenvironment. Finally, the immunity modulation effects of SCC15+PLHCu@Gel were evaluated on the enhancement of tumor-infiltrating cytotoxic CD8+ T cells, maturation of dendritic cells as well as inhibition of immunosuppressive Tregs and MDSCs. These enhanced antitumor immunity responses might be related to the immunogenic cell death (ICD) effects. Thereby, this study presents a promising therapeutic strategy for targeting the ECM and enhancing the immune responses against pancreatic Cancer.

Keywords

Disulfiram derivative CPD12C15; Immunity enhancement; Microenvironment remodeling; Pancreatic cancer; Thermosensitive hydrogel; extracellular matrix targeting.

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