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Metabolic Homeostasis-Regulated Nanoparticles for Antibody-Independent Cancer Radio-Immunotherapy
Wenhao Shen1, Teng Liu1, Pei Pei1
1State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, Jiangsu, 215123, China.
Abstract:
The special metabolic traits of cancer cells and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) are promising targets for developing novel cancer therapy strategies, especially the glycolysis and mitochondrial energy metabolism. However, therapies targeting a singular metabolic pathway are always counteracted by the metabolic reprogramming of cancer, resulting in unsatisfactory therapeutic effect. Herein, this work employs poly(ethylene glycol)-coated (PEGylated) liposomes as the drug delivery system for both mannose and levamisole hydrochloride to simultaneously inhibit glycolysis and restrain mitochondrial energy metabolism and thus inhibit tumor growth. In combination with radiotherapy, the liposomes can not only modulate the immunosuppressive TME by cellular metabolism regulation to achieve potent therapeutic effect for local tumors, but also suppress the M2 macrophage proliferation triggered by X-ray irradiation and thus enhance the immune response to inhibit metastatic lesions. In brief, this work provides a new therapeutic strategy targeting the special metabolic traits of cancer cells and immunosuppressive TAMs to enhance the abscopal effect of radiotherapy for cancer.
Insights
This study developed PEGylated liposomes to inhibit cancer cell glycolysis and mitochondrial metabolism. Combined with radiotherapy, this approach enhances anti-tumor immunity and suppresses metastasis.
Area of Science:
- Oncology
- Cancer Metabolism
- Drug Delivery Systems
Background:
- Cancer cells and tumor-associated macrophages (TAMs) exhibit unique metabolic pathways, including glycolysis and mitochondrial respiration, presenting therapeutic targets.
- Targeting single metabolic pathways often leads to cancer's metabolic reprogramming and treatment failure.
- The tumor microenvironment (TME) is often immunosuppressive, hindering effective cancer therapy.
Purpose of the Study:
- To develop a novel drug delivery system for simultaneous inhibition of cancer cell glycolysis and TAM mitochondrial metabolism.
- To evaluate the efficacy of this strategy in combination with radiotherapy for local tumor control and metastatic suppression.
- To investigate the modulation of the immunosuppressive TME and enhancement of anti-tumor immune responses.
Main Methods:
- Utilized poly(ethylene glycol)-coated (PEGylated) liposomes encapsulating mannose and levamisole hydrochloride.
- Administered liposomes to simultaneously inhibit glycolysis and mitochondrial energy metabolism in cancer cells and TAMs.
- Combined liposome treatment with radiotherapy to assess effects on local tumors and metastatic lesions.
Main Results:
- The PEGylated liposomes effectively inhibited both glycolysis and mitochondrial metabolism in cancer cells and TAMs.
- Combination therapy demonstrated potent therapeutic effects on local tumors by modulating the TME.
- The treatment suppressed M2 macrophage proliferation post-radiotherapy, enhancing immune response and inhibiting metastatic lesions.
Conclusions:
- Simultaneous targeting of cancer cell and TAM metabolism via PEGylated liposomes offers a promising therapeutic strategy.
- Combination with radiotherapy enhances the abscopal effect by modulating the TME and boosting anti-tumor immunity.
- This approach represents a novel strategy to overcome metabolic reprogramming and improve cancer treatment outcomes.
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