Dual-Responsive Nanomedicine Activates Programmed Antitumor Immunity through Targeting Lymphatic System

Area of Science:

• Immunology
• Nanomedicine
• Oncology

Background:

• Effective antitumor immunotherapy relies on initiating cancer-immune cycles within lymph nodes.
• Lymphatic drug delivery offers a promising strategy for activating antitumor immunity.

Purpose of the Study:

• To develop a pH- and enzyme-dual-responsive nanomedicine for programmed activation of antitumor immunity via lymphatic system delivery.
• To investigate the nanomedicine's ability to sequentially release therapeutic agents and trigger cascading immune responses.

Main Methods:

• A dual-responsive nanomedicine was designed to release a STING agonist in acidic lymph nodes.
• The nanomedicine binds to PD-1+ T cells for tumor-specific delivery, releasing an anti-PD-1 antibody.
• The nanomedicine delivers a DNA methylation inhibitor to tumor cells, inducing pyroptosis and immunogenic cell death.

Main Results:

• The nanomedicine successfully activated dendritic cells and T cells in lymph nodes.
• Targeted delivery to tumors was achieved via T cell hitchhiking.
• Combined therapies (STING agonism, ICB, pyroptosis) demonstrated significant antitumor effects in a 4T1 breast tumor model.

Conclusions:

• The developed nanomedicine effectively orchestrates a cascade of antitumor immune responses.
• This approach creates a positive feedback loop, enhancing immunotherapy outcomes.
• The study highlights the potential of programmed nanomedicine for synergistic cancer treatment.