Targeted Intracellular Copper Reservoir Enhances Liver Cancer Immunotherapy

Area of Science:

• Biomedical Engineering
• Cancer Research
• Immunotherapy

Background:

• Hepatocellular carcinoma (HCC) is a "cold tumor" with low immunogenicity, leading to poor responses to conventional immunotherapies.
• Modulating the tumor immune microenvironment (TIME) is crucial for enhancing cancer treatment efficacy.

Purpose of the Study:

• To develop sono-activatable nanoparticles (STCNs) that induce endogenous cuproptosis for enhanced immunotherapy in HCC.
• To investigate the potential of STCNs in reprogramming the TIME and potentiating anti-cancer immune responses.

Main Methods:

• Fabrication of N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN)-encapsulated cancer-targeted nanoparticles (STCNs).
• Ultrasound irradiation to trigger TPEN release, copper chelation, and subsequent reactive oxygen species (ROS) generation.
• Evaluation of cuproptosis induction, immunogenic cell death (ICD), and T lymphocyte infiltration in HCC models.
• Combination therapy assessment with anti-programmed cell death protein 1 (PD1) in vivo.

Main Results:

• STCNs were effectively internalized by HCC cells via folate-mediated endocytosis.
• Ultrasound-triggered TPEN release initiated a cascade leading to cuproptosis, ROS production, and ICD.
• The STCNs combined with anti-PD1 therapy demonstrated significant anti-tumor efficacy in vivo and in other solid tumor models.

Conclusions:

• Endogenous cuproptosis immunopromotion via STCNs is a viable strategy to overcome the challenges of 'cold tumors'.
• This approach effectively reprograms the tumor immune microenvironment, enhancing immunotherapy outcomes.
• The developed strategy holds broad therapeutic potential for various solid tumors, offering a promising new avenue for cancer treatment.