G-Quadruplex-Modular CpG Nanoplatform Drives Multi-Pathway Immunity for Abscopal Chemoimmunotherapy.

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Immunology

Background:

• Conventional cancer immunotherapy faces challenges like weak immune activation, immunosuppressive tumor microenvironments (TME), and rapid CpG adjuvant degradation.
• Existing treatments often fail to achieve sustained immune responses or effectively overcome tumor-induced immune suppression.

Purpose of the Study:

• To develop a G-quadruplex (G4)-modular CpG nanoplatform (IONP-G4-DOX/IMT) to enhance cancer immunotherapy.
• To address limitations of current immunotherapies by improving CpG stability, inducing immunogenic cell death (ICD), and activating the cGAS-STING pathway.

Main Methods:

• Fabrication of a nanoplatform using iron oxide nanoparticles (IONPs) as a core, with G4 as a multifunctional module.
• Integration of CpG for sustained TLR9 activation, doxorubicin (DOX) for ICD and antigen release, and IMT for cGAS-STING pathway activation.
• Evaluation of the nanoplatform's efficacy in murine 4T1 breast cancer models.

Main Results:

• The IONP-G4-DOX/IMT nanoplatform demonstrated enhanced CpG nuclease resistance and sustained TLR9 activation.
• It successfully induced immunogenic cell death (ICD), released tumor antigens, and activated the cGAS-STING pathway.
• Significant tumor suppression (79.4%) was observed in murine models with no major systemic toxicity, alongside the induction of long-term antitumor immunity.

Conclusions:

• The developed G4-modular CpG nanoplatform offers a synergistic approach to overcome key challenges in cancer immunotherapy.
• This strategy effectively reprograms the tumor microenvironment, enhances T cell responses, and achieves substantial tumor suppression.
• IONP-G4-DOX/IMT presents a promising platform for advanced abscopal chemoimmunotherapy with potential for treating advanced cancers.