Journal
ADVANCED SCIENCE
Volume 9, Issue 17, Pages -Publisher
WILEY
DOI: 10.1002/advs.202105376
Keywords
AMPK activation; ATP-adenosine pathway; CD39 inhibition; exosome; immunnometabolic therapy
Categories
Funding
- Guangdong basic and Applied Basic Research Fund Regional Joint Fund Project (key project) [2020B1515120091]
- Shenzhen Basic Research Special (Natural Science Fund) basic research surface project [JCYJ20210324113006017]
- Shenzhen Key Medical Discipline Construction Fund [SZXK015]
- Science, Technology & Innovation Commission of Shenzhen Municipality [JCYJ20190807144209381]
- National Natural Science Foundation of China [32170717, 81901771]
- Cancer research and translational platform project of Zhongnan Hospital of Wuhan University [ZLYNXM202004]
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Targeting intratumoral dysregulated metabolism pathways has shown promise in reinvigorating antitumor immunity. This study reports a nanocarrier-assisted immunometabolic therapy strategy that targets the ATP-adenosine axis for metabolic reprogramming of the tumor microenvironment. It demonstrates increased pro-inflammatory extracellular ATP levels and enhanced antitumor immune responses.
Metabolic interventions via targeting intratumoral dysregulated metabolism pathways have shown promise in reinvigorating antitumor immunity. However, approved small molecule immunomodulators often suffer from ineffective response rates and severe off-target toxicity. ATP occupies a crucial role in energy metabolism of components that form the tumor microenvironment (TME) and influences cancer immunosurveillance. Here, a nanocarrier-assisted immunometabolic therapy strategy that targets the ATP-adenosine axis for metabolic reprogramming of TME is reported. An ecto-enzyme (CD39) antagonist POM1 and AMP-activated protein kinase (AMPK) agonist metformin are both encapsulated into cancer cell-derived exosomes and used as nanocarriers for tumor targeting delivery. This method increases the level of pro-inflammatory extracellular ATP (eATP) while preventing the accumulation of immunosuppressive adenosine and alleviating hypoxia. Elevated eATP triggers the activation of P2X7-NLRP3-inflammasome to drive macrophage pyroptosis, potentiates the maturation and antigen capacity of dendritic cells (DCs) to enhance the cytotoxic function of T cells and natural killer (NK) cells. As a result, synergistic antitumor immune responses are initiated to suppress tumor progress, inhibit tumor distant metastases, provide long-term immune memory that offers protection against tumor recurrence and overcome anti-PD1 resistance. Overall, this study provides an innovative strategy to advance eATP-driven antitumor immunity in cancer therapy.
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