Synergistic Chemoimmunotherapy Augmentation via Sequential Nanocomposite Hydrogel-Mediated Reprogramming of Cancer-Associated Fibroblasts in Osteosarcoma

Hui Wang, Yu Chen, Ran Wei*, Jinlong Zhang, Jiahui Zhu, Wenbin Wang, Zhenfei Wang, Zulpikar Wupur, Yujing Li*, Huan Meng*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

In osteosarcoma, immunotherapy often faces hurdles posed by cancer-associated fibroblasts (CAFs) that secrete dense extracellular matrix components and cytokines. Directly removing CAFs may prove ineffective and even promote tumor metastasis. To address this challenge, a sequential nanocomposite hydrogel that reshapes CAF behavior is developed, enhancing tumor-infiltrating T-cells in osteosarcoma. The approach utilizes an injectable blend of carboxymethyl chitosan and tetrabasic polyethylene glycol, forming a hydrogel for controlled release of a potent CAF suppressor (Nox4 inhibitor, Nox4i) and liposomal Doxorubicin (L-Dox) to induce immunogenic cell death (ICD) upon in situ administration. Nox4i effectively counters CAF activation, overcoming T-cell exclusion mechanisms, followed by programmed L-Dox release for ICD induction in stroma-rich osteosarcoma models. Combining the co-delivery gel with αPD-1 checkpoint inhibitor further enhances its effectiveness in an orthotopic osteosarcoma model. Immunophenotyping data underscore a significant boost in tumor T-cell infiltration and favorable anti-tumor immunity at the whole-animal level.

Original languageEnglish
Article number2309591
JournalAdvanced Materials
Volume36
Issue number15
DOIs
Publication statusPublished - 11 Apr 2024

Keywords

  • Nox4 inhibition
  • cancer-associated fibroblasts
  • chemoimmunotherapy
  • osteosarcoma
  • sequential nanocomposite hydrogels

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