Cannabidiol (CBD) as a novel inhibitor of HLA-G expression in human choriocarcinoma cell line (JEG-3)

Cannabinoids have emerged as promising agents in cancer research due to their antitumor properties. While their effects on tumor growth and survival are well documented, their influence on immune checkpoint regulation remains poorly understood. Here, we investigated the effects of cannabidiol (CBD) and a high-CBD extract (CBD-HCE) on HLA-G expression in human choriocarcinoma JEG-3 cells, a non-classical HLA class I molecule linked to tumor immune escape. Safe concentrations of CBD and CBD-HCE were determined by MTT assays. Apoptosis (Caspase-3), proliferation (Ki-67), and migration (wound healing and MMP-9 immunostaining) were assessed, and HLA-G expression was quantified by RT-qPCR and immunocytochemistry. Both CBD and CBD-HCE reduced cell proliferation and migration, increased apoptosis, and significantly downregulated HLA-G expression at both the mRNA and protein levels. This inhibitory effect was dose- and time-dependent, and fully reversible after treatment withdrawal, indicating a dynamic and CBD-dependent modulation. These results provide the first experimental evidence of HLA-G downregulation by CBD and CBD-HCE, highlighting a novel immunomodulatory mechanism with potential therapeutic implications. By simultaneously impairing tumor viability and reversing immune evasion, CBD-based compounds may enhance antitumor immunity and potentiate immunotherapy efficacy. Further research involving additional tumor cell lines, in vivo models, and immune-relevant systems are necessary to validate and expand upon these findings.