This study designed a multifunctional nanovaccine based on poly(lactic acid) (PLA) capable of co-delivering tumor-associated antigens, TLR ligands, and siRNA targeting TGF-β1. When combined with an OX40 agonistic antibody, it significantly improved the anti-tumor immune response in triple-negative breast cancer (TNBC) and luminal B-like breast cancer models, offering a novel strategy to enhance response rates to immunotherapy in TNBC patients.
Literature Overview
This article, 'Multifunctional Nanovaccine Sensitizes Breast Cancer to Immune Checkpoint Therapy', published in the journal Advanced Functional Materials, reviews the challenges in immunotherapy for triple-negative breast cancer (TNBC) and proposes a polymer nanoparticle-based multifunctional nanovaccine. By targeting TGF-β1 in dendritic cells (DCs) and activating OX40 signaling, it remodels the tumor microenvironment (TME) to enhance anti-tumor immune responses.
Background Knowledge
TNBC is a subtype of breast cancer lacking expression of estrogen receptor (ER), progesterone receptor (PR), and HER2. It is among the most difficult-to-treat breast cancers due to its aggressive nature, high risk of early recurrence, and limited treatment options. While PD-1/PD-L1 inhibitors have brought hope to some TNBC patients in recent years, the overall response rate remains low. OX40 is a co-stimulatory T cell receptor that enhances T cell expansion, survival, and pro-inflammatory cytokine secretion while inhibiting the immunosuppressive function of regulatory T cells (Tregs). However, monotherapy with OX40 agonists has shown limited efficacy in preclinical models, suggesting the need for combinatorial strategies to improve therapeutic outcomes. Nanovaccines, as an emerging cancer immunotherapy approach, can target DCs and induce antigen-specific immune responses but require optimization for TNBC applications. This study aims to overcome immunosuppression within the TME by constructing a multifunctional nanoparticle integrating antigen, TLR ligands, and siTGF-β1, in combination with OX40 stimulation, to enhance anti-tumor efficacy.
Research Methods and Experiments
Researchers developed a poly(lactic acid) (PLA)-based nanoparticle (NP) using a double emulsion solvent evaporation method. The NP efficiently co-encapsulated tumor-associated antigens (e.g., α-Lac and OVA), TLR ligands (CpG-ODN and Poly(I:C)), and siRNA targeting TGF-β1. The cellular uptake efficiency was evaluated using flow cytometry and confocal microscopy, revealing efficient internalization in both dendritic and tumor cells. The anti-tumor efficacy of NP combined with OX40 agonistic antibody (αOX40) was assessed in a 4T1 TNBC mouse model, focusing on tumor growth curves, survival rates, immune cell infiltration, and TGF-β1 expression levels.
Key Conclusions and Perspectives
Research Significance and Prospects
This study presents a novel nanovaccine platform capable of synergizing with OX40 agonists to enhance anti-tumor immune responses, offering a potential immunotherapy strategy for TNBC and other difficult-to-treat breast cancers. Future research should focus on optimizing the delivery method of the vaccine and evaluating its safety and efficacy in preclinical models to facilitate clinical translation.
Conclusion
This study developed a multifunctional nanovaccine capable of co-delivering antigen, TLR ligands, and siTGF-β1, effectively activating dendritic cells and remodeling the tumor microenvironment. As a result, the therapeutic efficacy of OX40 agonists was significantly enhanced in TNBC and luminal B-like breast cancer models. This strategy not only provides new treatment options for TNBC patients but also lays the foundation for further optimization and clinical translation of cancer nanovaccines. The findings suggest that combining nanovaccines with immune checkpoint agonists may represent an important direction in future cancer immunotherapy.
