Asiaticoside modulates human NK cell functional fate by mediating metabolic flexibility in the tumor microenvironment.

Background: Transforming growth factor-beta (TGF-β), an immunosuppressive cytokine, is often elevated in various tumors and inhibits the immune system's ability to combat tumor cells. Despite promising results from TGF-β inhibitor therapies, their clinical efficacy remains limited.
Purpose: This study aimed to enhance the antitumor capabilities of natural killer (NK) cells in the presence of TGF-β by exploring the potential of asiaticoside, a natural compound with established clinical safety.
Study Design: The effects of asiaticoside on NK cells were investigated to determine its potential to counteract TGF-β-induced immunosuppression and elucidate the underlying mechanisms.
Methods: Natural compounds were screened using a Luminex assay to identify those promoting Interferon-γ (IFN-γ) secretion from NK cells. Asiaticoside-pretreated NK cells' cytotoxicity was assessed against K562, OVCAR8, and A2780 cells using organoids from ascites-derived ovarian cancer (OC) cells. In vivo efficacy was evaluated with B16 melanoma lung metastasis and subcutaneous tumor models in C57BL/6 mice, using asiaticoside as a 50 mg/kg injection. The compound's ability to enhance NK cell-driven anti-neoplastic responses was further assessed in an OC murine model. Effects on TGF-β/SMAD pathways and mitochondrial functions were examined through various microscopy and metabolomic techniques. The involvement of the mTOR/DRP1 axis in asiaticoside-mediated restoration of mitochondrial oxidation in NK cells after TGF-β suppression was determined using the mTOR inhibitor rapamycin and the DRP1 inhibitor Mdivi-1.
Results: Asiaticoside-treated NK cells retained their ability to suppress tumor growth and metastasis despite TGF-β presence. Asiaticoside downregulated TGF-β receptors 1 (TGFBR1) expression, impaired the protein stability of TGFBR1 and TGF-β receptors 2 (TGFBR2), and reduced SMAD2 phosphorylation, preventing SMAD2 translocation from the mitochondria. This preserved mitochondrial respiration and maintained NK cell antitumor activity.
Conclusion: The study concludes that asiaticoside has significant potential as a strategy for "priming" NK cells in cellular immunotherapy. By demonstrating that asiaticoside degrades the TGF-β receptor, leading to reduced phosphorylation of SMAD2 and preventing its mitochondrial translocation, thereby maintaining mitochondrial integrity. Meantime, asiaticoside counteracts TGF-β-induced suppression of mitochondrial oxidative and aerobic respiration through the mTOR/DRP1 pathways. The research uncovers a previously unreported pathway for preserving mitochondrial respiration and NK cell functionality. A detailed mechanistic insight into how asiaticoside functions at the molecular level was explored. Its ability to counteract the immunosuppressive effects of TGF-β makes it a valuable candidate for enhancing the effectiveness of immunotherapies in treating a variety of tumors with elevated TGF-β levels.
Competing Interests: Declaration of competing interest We are submitting our manuscript titled " Asiaticoside modulates human NK cell functional fate by mediating metabolic flexibility in the tumor microenvironment" for publication consideration in the esteemed "Phytomedicine". The authors declare that they have no competing interests.
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