Orchestrated metal-coordinated carrier-free celastrol hydrogel intensifies T cell activation and regulates response to immune checkpoint blockade for synergistic chemo-immunotherapy

Biomaterials. 2025 Jan:312:122723. doi: 10.1016/j.biomaterials.2024.122723. Epub 2024 Jul 31.

Abstract

The challenges generated by insufficient T cell activation and infiltration have constrained the application of immunotherapy. Making matters worse, the complex tumor microenvironment (TME), resistance to apoptosis collectively poses obstacles for cancer treatment. The carrier-free small molecular self-assembly strategy is a current research hotspot to overcome these challenges. This strategy can transform multiple functional agents into sustain-released hydrogel without the addition of any excipients. Herein, a coordination and hydrogen bond mediated tricomponent hydrogel (Cel hydrogel) composed of glycyrrhizic acid (GA), copper ions (Cu2+) and celastrol (Cel) was initially constructed. The hydrogel can regulate TME by chemo-dynamic therapy (CDT), which increases reactive oxygen species (ROS) in conjunction with GA and Cel, synergistically expediting cellular apoptosis. What's more, copper induced cuproptosis also contributes to the anti-tumor effect. In terms of regulating immunity, ROS generated by Cel hydrogel can polarize tumor-associated macrophages (TAMs) into M1-TAMs, Cel can induce T cell proliferation as well as activate DC mediated antigen presentation, which subsequently induce T cell proliferation, elevate T cell infiltration and enhance the specific killing of tumor cells, along with the upregulation of PD-L1 expression. Upon co-administration with aPD-L1, this synergy mitigated both primary and metastasis tumors, showing promising clinical translational value.

Keywords: Carrier free small molecule hydrogel; Celastrol; Chemo-immunotherapy; Cuproptosis; Immune regulation; Tumor microenvironment.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Copper* / chemistry
  • Female
  • Glycyrrhizic Acid / chemistry
  • Glycyrrhizic Acid / pharmacology
  • Humans
  • Hydrogels* / chemistry
  • Immune Checkpoint Inhibitors* / pharmacology
  • Immune Checkpoint Inhibitors* / therapeutic use
  • Immunotherapy* / methods
  • Lymphocyte Activation* / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Pentacyclic Triterpenes* / pharmacology
  • Reactive Oxygen Species* / metabolism
  • T-Lymphocytes* / drug effects
  • T-Lymphocytes* / immunology
  • Triterpenes / chemistry
  • Triterpenes / pharmacology
  • Tumor Microenvironment* / drug effects

Substances

  • celastrol
  • Pentacyclic Triterpenes
  • Hydrogels
  • Immune Checkpoint Inhibitors
  • Copper
  • Reactive Oxygen Species
  • Glycyrrhizic Acid
  • Triterpenes