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Mitoxantrone Combined with Engineered TRAIL-Nanovesicles for Enhanced Cancer Immunotherapy Via Converting Apoptosis
Yi Wang1, Boning Niu1, Yinmei Tian1
1Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, 430030, China.
Abstract:
Pyroptosis, a highly inflammatory form of programmed cell death, has emerged as a promising target for cancer immunotherapy. However, in the context of pyroptosis execution, while both caspase-3 and GSDME are essential, it is noteworthy that GSDME is frequently under-expressed in cold tumors. To overcome this limitation, engineered cellular nanovesicles (NVs) presenting TRAIL on their membranes (NVTRAIL) are developed to trigger the upregulation of cleaved caspase-3. When strategically combined with the chemotherapeutic agent mitoxantrone (MTO), known for its ability to enhance GSDME expression, MTO@NVTRAIL can convert cancer cells from apoptosis into pyroptosis, inhibit the tumor growth and metastasis successfully in primary tumor. The microparticles released by pyroptotic tumor cells also exhibited certain cytotoxicity against other tumor cells. In addition, tumor cells exposed to the combination treatment of MTO@NVTRAIL in vitro have also demonstrated potential utility as a novel form of vaccine for cancer immunotherapy. Flow analysis of the tumor microenvironment and draining lymph nodes reveals an increased proportion of matured dendritic cells and activation of T cells. In summary, the research provided a reference and alternative approach to induce cancer pyroptosis for clinical antitumor therapy based on engineered cellular nanovesicles and chemotherapy.
Insights
Engineered nanovesicles combined with chemotherapy induce pyroptosis, a cell death pathway, to inhibit cancer growth and metastasis. This approach also shows potential as a cancer vaccine by activating immune cells.
Area of Science:
- Biomedical Engineering
- Cancer Research
- Immunotherapy
Background:
- Pyroptosis, an inflammatory cell death, is a promising cancer immunotherapy target.
- GSDME under-expression in tumors limits pyroptosis induction.
- Caspase-3 and GSDME are essential for pyroptosis execution.
Purpose of the Study:
- To develop a strategy for inducing pyroptosis in tumors.
- To overcome GSDME under-expression in cold tumors.
- To evaluate the therapeutic potential of engineered nanovesicles and chemotherapy combination.
Main Methods:
- Engineered cellular nanovesicles (NVs) presenting TRAIL (NVTRAIL) were developed.
- NVTRAIL were combined with mitoxantrone (MTO) to create MTO@NVTRAIL.
- The combination therapy's efficacy was assessed in primary tumors and its immunotherapeutic potential evaluated.
Main Results:
- MTO@NVTRAIL successfully inhibited tumor growth and metastasis by converting apoptosis to pyroptosis.
- Microparticles from pyroptotic cells showed cytotoxicity against other tumor cells.
- The treatment increased mature dendritic cells and activated T cells in the tumor microenvironment and draining lymph nodes.
Conclusions:
- Engineered nanovesicles combined with chemotherapy offer an alternative approach to induce cancer pyroptosis.
- This strategy shows potential for clinical antitumor therapy and cancer immunotherapy.
- The combination treatment demonstrated efficacy in inhibiting tumor progression and activating anti-tumor immunity.
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