Iron Oxide Nanoparticles Inhibit Tumor Progression and Suppress Lung Metastases in Mouse Models of Breast Cancer
Preethi Korangath1, Lu Jin2, Chun-Ting Yang1
1Department of Radiation Oncology and Molecular Radiation Sciences, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21231, United States.
Abstract:
Systemic exposure to starch-coated iron oxide nanoparticles (IONPs) can stimulate antitumor T cell responses, even when little IONP is retained within the tumor. Here, we demonstrate in mouse models of metastatic breast cancer that IONPs can alter the host immune landscape, leading to systemic immune-mediated disease suppression. We report that a single intravenous injection of IONPs can inhibit primary tumor growth, suppress metastases, and extend survival. Gene expression analysis revealed the activation of Toll-like receptor (TLR) pathways involving signaling via Toll/Interleukin-1 receptor domain-containing adaptor-inducing IFN-β (TRIF), a TLR pathway adaptor protein. Requisite participation of TRIF in suppressing tumor progression was demonstrated with histopathologic evidence of upregulated IFN-regulatory factor 3 (IRF3), a downstream protein, and confirmed in a TRIF knockout syngeneic mouse model of metastatic breast cancer. Neither starch-coated polystyrene nanoparticles lacking iron, nor iron-containing dextran-coated parenteral iron replacement agent, induced significant antitumor effects, suggesting a dependence on the type of IONP formulation. Analysis of multiple independent clinical databases supports a hypothesis that upregulation of TLR3 and IRF3 correlates with increased overall survival among breast cancer patients. Taken together, these data support a compelling rationale to re-examine IONP formulations as harboring anticancer immune (nano)adjuvant properties to generate a therapeutic benefit without requiring uptake by cancer cells.
Insights
Starch-coated iron oxide nanoparticles (IONPs) stimulate immune responses to suppress breast cancer growth and metastasis. This immune activation, mediated by Toll-like receptor (TLR) pathways, offers a novel therapeutic strategy.
Area of Science:
- Nanomedicine
- Immunology
- Oncology
Background:
- Systemic exposure to iron oxide nanoparticles (IONPs) can elicit antitumor T cell responses.
- The precise mechanisms by which IONPs modulate the immune system for cancer suppression are not fully understood.
Purpose of the Study:
- To investigate the potential of starch-coated IONPs to induce systemic immune-mediated suppression of metastatic breast cancer.
- To elucidate the underlying immune pathways involved in the antitumor effects of IONPs.
Main Methods:
- Utilized mouse models of metastatic breast cancer to assess the therapeutic effects of IONPs.
- Performed gene expression analysis to identify activated immune signaling pathways.
- Employed TRIF knockout mice to confirm the role of Toll/Interleukin-1 receptor domain-containing adaptor-inducing IFN-β (TRIF) pathway.
- Analyzed clinical databases to correlate immune markers with patient survival.
Main Results:
- A single intravenous injection of starch-coated IONPs inhibited primary tumor growth, suppressed metastases, and extended survival in mouse models.
- IONP treatment activated Toll-like receptor (TLR) pathways, specifically via TRIF and downstream IFN-regulatory factor 3 (IRF3).
- TRIF was essential for the tumor-suppressive effects of IONPs, as confirmed in TRIF knockout mice.
- Non-iron-containing nanoparticles and a different iron formulation did not show significant antitumor effects, indicating formulation-specific activity.
- Clinical data analysis suggested a correlation between TLR3 and IRF3 upregulation and increased overall survival in breast cancer patients.
Conclusions:
- Starch-coated IONPs possess anticancer immune (nano)adjuvant properties, inducing systemic immune-mediated disease suppression.
- The therapeutic efficacy of IONPs is dependent on their formulation and relies on the TRIF-mediated TLR pathway activation.
- IONPs may offer a novel therapeutic approach for breast cancer, generating benefits without direct tumor cell uptake.
