CB2R activation enhances tumor-associated macrophages-mediated phagocytosis of glioma cell.

Background: Cannabinoid administration has demonstrated promising anti-tumor effects for glioblastoma (GBM) by inhibiting glioma cell proliferation and inducing glioma cell death. However, the impact of cannabinoids and endocannabinoid receptors on immune cells within the tumor microenvironment (TME) remains largely unexplored. Tumor-associated macrophages (TAMs), the most abundant immune cells in the TME, and their mediated phagocytosis of tumor cells have shown potential in preclinical xenografts of various human malignancies. This study aimed to investigate the effect and mechanism of endocannabinoid receptor 2 (CB2R) on TAMs-mediated phagocytosis in xenografted mice with GL261-GFP cell lines. Methods: We measured the phagocytic activity using immunofluorescence and flow cytometry, and we used the IVIS Spectrum System for bioluminescent imaging to track the growth of the tumor. Results: Our findings demonstrated that administering JWH133, a selective CB2R agonist, significantly boosted TAMs-mediated phagocytosis. However, administering AM630, a selective CB2R antagonist, significantly inhibited TAMs-mediated phagocytosis. Mechanistically, CB2R activation upregulated the expression of CD36 on TAMs, a scavenger receptor known to facilitate phagocytosis. Furthermore, sulfo-N-succinimidyl oleate (SSO), an irreversible CD36 inhibitor, could reverse the CB2R activation-induced enhancement of phagocytosis by TAMs. Additionally. JHW133 also effectively augmented the chemotherapeutic efficacy of temozolomide. Conclusion: Overall, our findings show that CB2R activation promotes TAMs-mediated phagocytosis of tumor cells by enhancing CD36 expression, implying that JWH133 could be a useful therapeutic approach to improving chemotherapeutic efficacy against GBM.