Circulating immunotherapy strategy based on pyroptosis and STING pathway: Mn-loaded paclitaxel prodrug nanoplatform against tumor progression and metastasis
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Published on: May 22, 2020
Bingjie Wang1, Teng Wang1, Tianze Jiang2
1Key Laboratory of Marine Drugs, Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycoengineering, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
Abstract:
Immunotherapy has emerged as a promising strategy against tumors. However, its efficacy is limited by low immunogenicity, poor antigen presentation, and inadequate lymphocyte infiltration. Herein, we develop a nanoplatform (Mn-HSP) loaded with manganese ions (Mn2+) and paclitaxel (PTX) prodrug based on hyaluronic acid. PTX in Mn-HSP induces DNA damage and pyroptosis to release tumor-associated antigens (TAAs), enhancing tumor-specific adaptive immunity. Meanwhile, Mn2+ in Mn-HSP, together with PTX-induced DNA damage, activates the stimulator of interferon gene (STING) pathway to amplify innate immunity. Mn-HSP combines with adaptive and innate immunity, effectively enhancing the presentation of antigen-presenting cells (APCs) and promoting tumor infiltration of cytotoxic T lymphocytes (CTLs). In turn, the granzyme B (GZMB) secreted by CTLs triggers pyroptosis again, thereby establishing a "circulating immunotherapy" against tumors. Our results demonstrate that Mn-HSP efficiently inhibits primary breast tumors, as well as rechallenge tumors and lung metastasis in vivo. Therefore, the circulating immunotherapy that combines pyroptosis mediated adaptive immunity and STING pathway amplified innate immunity provides a novel strategy for enhancing tumor immunotherapy.
Insights
This study introduces Mn-HSP, a novel nanoplatform that enhances cancer immunotherapy by combining pyroptosis-mediated adaptive immunity and STING pathway-activated innate immunity. Mn-HSP effectively inhibits primary tumors, rechallenge tumors, and metastasis.
Area of Science:
- Oncology
- Immunology
- Nanotechnology
- Drug Delivery
Background:
- Immunotherapy shows promise for cancer treatment but faces limitations like low immunogenicity and poor lymphocyte infiltration.
- Existing strategies struggle to effectively stimulate both innate and adaptive immune responses against tumors.
Purpose of the Study:
- To develop a novel nanoplatform (Mn-HSP) for enhanced cancer immunotherapy.
- To investigate the synergistic effects of manganese ions (Mn2+) and paclitaxel (PTX) in stimulating anti-tumor immunity.
Main Methods:
- A hyaluronic acid-based nanoplatform (Mn-HSP) was engineered, co-delivering Mn2+ and a PTX prodrug.
- The study evaluated Mn-HSP's ability to induce DNA damage, pyroptosis, TAA release, and STING pathway activation.
- In vivo studies assessed Mn-HSP's efficacy against primary tumors, rechallenge tumors, and lung metastasis in a mouse model.
Main Results:
- Mn-HSP treatment induced DNA damage and pyroptosis, leading to tumor-associated antigen release and enhanced adaptive immunity.
- Co-delivery of Mn2+ and PTX activated the STING pathway, amplifying innate immune responses.
- Mn-HSP significantly improved antigen-presenting cell function and cytotoxic T lymphocyte infiltration, leading to tumor inhibition and reduced metastasis.
Conclusions:
- The developed Mn-HSP nanoplatform establishes a "circulating immunotherapy" by integrating pyroptosis-induced adaptive immunity and STING-amplified innate immunity.
- This combined approach offers a novel and effective strategy for overcoming current limitations in cancer immunotherapy.
- Mn-HSP demonstrated significant efficacy in inhibiting tumor growth and metastasis in vivo, highlighting its therapeutic potential.
