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Updated: Jun 2, 2025
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
Promotion of triple negative breast cancer immunotherapy by combining bioactive radicals with immune checkpoint
Meixu Chen1, Linlin Song2, Yao Zhou1
1Institute of Breast Health Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, 610041, China.
Abstract:
Although immunotherapy has revolutionized clinical cancer treatment, the efficacy is limited due to the lack of tumor-associated antigens (TAAs) and the presence of compensatory immune checkpoints. To overcome the deficiency, a nano-system loaded with ozone and CD47 inhibitor RRx-001 is designed and synthesized. Upon irradiation, reactive oxygen species (ROS) generated from ozone reacts with nitric oxide (NO) metabolized from RRx-001 to form reactive nitrogen species (RNS), which presents a much stronger cell-killing ability than ROS. Molecular mechanism studies further reveal that RNS induce extensive immunogenic cell death (ICD). The released TAAs promote infiltration of cytotoxic T lymphocytes, which provides the basis for immune checkpoint blockade (ICB) therapy. Meanwhile, RRx-001 carried by the nanoparticles and the produced radicals repolarize M2-type tumor-associated macrophages (TAMs) into the anti-tumor M1-type, consequently reversing the immunosuppressive tumor microenvironment (TME). In a xenograft triple-negative breast cancer (TNBC) animal model, O3-001@lipo (liposome enwrapping O3 and RRx-001) plus irradiation shows a significant anti-tumor efficacy by improving cytotoxic lymphocyte infiltration and regulating immunosuppressive TME. In summary, the O3-001@lipo nano-system triggered by irradiation potently improves the efficacy of immunotherapy by introducing strong cytotoxic RNS, which not only enriches the toolbox of ICD inducer but also provides a strategy of treatment for immune deficient tumor. STATEMENT OF SIGNIFICANCE: This study introduces a nano-system that leverages ozone and RRx-001 in the presence of X-ray irradiation to generate reactive nitrogen species, enhancing immunogenic cell death and promoting T-lymphocyte infiltration in triple-negative breast cancer, addressing a significant unmet need in the field. The scientific contribution is the development of a clinically translatable nano-system that not only induces ICD but also reshapes the tumor microenvironment, which is expected to have a profound impact on the readership in pharmaceutics, material science, and nano-bio interaction, particularly for those interested in advanced immune therapy approaches.
Insights
This study developed a novel nano-system combining ozone and RRx-001 to generate reactive nitrogen species, enhancing cancer immunotherapy. The treatment effectively triggers immunogenic cell death and promotes anti-tumor immune responses in triple-negative breast cancer models.
Area of Science:
- Oncology
- Immunotherapy
- Nanomedicine
- Material Science
Background:
- Immunotherapy efficacy is limited by insufficient tumor-associated antigens (TAAs) and immune checkpoints.
- Developing novel strategies to overcome tumor immunosuppression and enhance anti-tumor immune responses is crucial for effective cancer treatment.
Purpose of the Study:
- To design and synthesize a nano-system loaded with ozone and a CD47 inhibitor (RRx-001) to enhance cancer immunotherapy.
- To investigate the mechanism of action, including reactive nitrogen species (RNS) generation, immunogenic cell death (ICD) induction, and tumor microenvironment (TME) modulation.
- To evaluate the anti-tumor efficacy of the nano-system in a triple-negative breast cancer (TNBC) model.
Main Methods:
- Synthesis of a liposome-based nano-system encapsulating ozone (O3) and RRx-001 (O3-001@lipo).
- Irradiation of the nano-system to generate reactive oxygen species (ROS) and reactive nitrogen species (RNS) through the reaction of ozone with RRx-001-metabolized nitric oxide (NO).
- In vitro studies to assess RNS-induced ICD and macrophage repolarization (M2 to M1).
- In vivo evaluation in a TNBC xenograft mouse model to assess anti-tumor efficacy, T-lymphocyte infiltration, and TME modulation.
Main Results:
- The O3-001@lipo nano-system, upon irradiation, generated RNS with potent cell-killing ability, inducing extensive ICD.
- RNS promoted the release of TAAs, enhancing cytotoxic T lymphocyte infiltration and providing a basis for immune checkpoint blockade therapy.
- RRx-001 and generated radicals effectively repolarized M2 TAMs to M1, reversing the immunosuppressive TME.
- Significant anti-tumor efficacy was observed in the TNBC model, characterized by improved cytotoxic lymphocyte infiltration and a regulated immunosuppressive TME.
Conclusions:
- The O3-001@lipo nano-system is a promising strategy for enhancing immunotherapy by generating cytotoxic RNS and inducing ICD.
- This approach effectively overcomes limitations in current cancer immunotherapy by enriching ICD inducers and treating immune-deficient tumors.
- The developed nano-system offers a clinically translatable platform for advanced immunotherapy, with potential impact in pharmaceutics, material science, and nano-bio interaction.
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