Biomimetic Nanocarriers Guide Extracellular ATP Homeostasis to Remodel Energy Metabolism for Activating Innate and Adaptive Immunity System.
Long WuWei XieYang LiQiankun NiPeter TimashevMeng LyuLigang XiaYuan ZhangLingrong LiuYufeng YuanXing-Jie LiangQiqing ZhangPublished in: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2022)
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.
Keyphrases
- cancer therapy
- protein kinase
- immune response
- drug delivery
- nlrp inflammasome
- dendritic cells
- nk cells
- small molecule
- oxidative stress
- squamous cell
- physical activity
- inflammatory response
- early onset
- squamous cell carcinoma
- toll like receptor
- big data
- drug release
- signaling pathway
- bone marrow
- childhood cancer
- artificial intelligence
- free survival
- smoking cessation