A Multi-Functional Nanoadjuvant Coupling Manganese with Toll-Like 9 Agonist Stimulates Potent Innate and Adaptive...

Area of Science:

• Immunology
• Nanotechnology
• Oncology

Background:

• Toll-like 9 agonists (CpG) show limited effectiveness as tumor immunotherapy adjuvants due to insufficient anti-tumor immunity activation.
• Nutrient metal ions were explored to enhance CpG adjuvant efficacy.

Purpose of the Study:

• To identify metal ions that enhance CpG-mediated immune activation.
• To develop a novel nanoadjuvant (MPN/CpG) for improved tumor immunotherapy.
• To evaluate the efficacy of MPN/CpG in preclinical tumor models.

Main Methods:

• Screening of common nutrient metal ions (Mn²⁺, Cu²⁺, Ca²⁺, Mg²⁺, Zn²⁺, Fe³⁺, Al³⁺) for enhancing CpG activity.
• Self-assembly of manganese (Mn²⁺) and CpG with epigallocatechin gallate (EGCG) into a nanoadjuvant (MPN/CpG).
• In vivo studies using B16 melanoma-bearing mouse models to assess tumor inhibition, tumor microenvironment modulation, and immune responses.

Main Results:

• Mn²⁺ was identified as a key enhancer of CpG, augmenting the STING-NF-κB pathway for immune activation.
• Local delivery of MPN/CpG inhibited tumor growth, repolarized M2 tumor-associated macrophages (TAMs) to M1, and increased CD8⁺/CD4⁺ T lymphocyte and dendritic cell (DC) infiltration.
• MPN/CpG showed enhanced lymph node accumulation, CpG uptake, and DC activation compared to free CpG, inducing robust antigen-specific CD8⁺ T cell and humoral immunity.
• MPN/CpG vaccination with OVA antigen significantly delayed melanoma growth and extended survival in a prophylactic model.

Conclusions:

• MPN/CpG is a potent nanoadjuvant that enhances innate and adaptive anti-tumor immunity.
• The nanoadjuvant effectively reshapes the tumor microenvironment, promoting anti-tumor responses.
• MPN/CpG holds significant potential as a multifunctional platform for cancer immunotherapy.