Nucleus-Targeted Sonosensitizer Activates the cGAS-STING Pathway for Tumor Sonodynamic Immunotherapy

Area of Science:

• Biomedical Engineering
• Cancer Research
• Immunology

Background:

• The nucleus is vital for sonodynamic therapy (SDT) and antitumor immunity.
• Challenges exist in generating reactive oxygen species (ROS) in situ, damaging nuclei, and activating the cGAS-STING pathway for immune response.

Purpose of the Study:

• To develop a small molecule, TBzT-CPi, that amplifies nucleus-targeted SDT and cGAS-STING pathway-dependent immune stimulation.
• To investigate the efficacy of TBzT-CPi in inducing cancer cell death and modulating the tumor microenvironment.

Main Methods:

• Designed a D-A-π-A1 structured small molecule, TBzT-CPi.
• Utilized ultrasound irradiation to trigger ROS generation and nucleus accumulation of TBzT-CPi.
• Assessed DNA damage, immunogenic cell death (ICD), apoptosis, and immune cell activation (cytotoxic T lymphocytes, dendritic cells) in the tumor microenvironment.

Main Results:

• TBzT-CPi accumulated in the nucleus upon ultrasound irradiation, generating ROS in situ.
• Nucleus-targeting SDT induced DNA damage, apoptosis, and ICD in tumor cells.
• TBzT-CPi treatment modified the immunosuppressive tumor microenvironment by activating immune cells and secreting cytokines.

Conclusions:

• Nucleus-targeting SDT with TBzT-CPi effectively induces cancer cell death and enhances antitumor immunity.
• This strategy shows promise for developing novel sonosensitizers for sonodynamic immunotherapy.
• TBzT-CPi represents a potential therapeutic agent for cancer treatment by combining direct tumor cell killing with immune system activation.