Inhibition of extracellular vesicle secretion by cannabidiol: A promising approach for oral squamous cell carcinoma therapy

Cannabidiol (CBD), a bioactive phytochemical derived from Cannabis sativa, exhibits anti-inflammatory, antioxidant, and emerging antitumor properties. Oral squamous cell carcinoma (OSCC), the most common oral cancer, remains challenging to treat due to its aggressive nature and limited therapeutic options. Extracellular vesicles (EVs) have been increasingly recognized as key mediators of tumor progression, facilitating intercellular communication, remodeling the tumor microenvironment (TME), and promoting metastasis, angiogenesis, and chemoresistance in OSCC. This review discusses the pharmacological properties of CBD, including its bioavailability limitations, multi-target mechanisms, and potential for combination therapy. Notably, we explore the hypothesis that CBD may exert antitumor effects through modulation of EV secretion-a novel and underexplored mechanism in OSCC. Although direct evidence in OSCC models remains limited, studies in non-OSCC systems suggest that CBD influences EV biogenesis and release via pathways involving Wnt/β-catenin, STAT3 signaling, and mitochondrial calcium homeostasis. Based on these findings, we propose a hypothetical framework linking CBD-mediated EV modulation to OSCC therapy. Despite its therapeutic promise, the clinical translation of CBD faces key hurdles, including poorly characterized mechanisms of EV regulation in OSCC, a lack of targeted delivery systems that compromises specificity and bioavailability, and a general scarcity of OSCC-specific evidence. This review underscores the urgent need for future research to prioritize long-term evaluations, explore synergistic CBD-drug combinations, develop advanced CBD delivery systems, and assess its dual role in tumor suppression and pain management to enable clinical use.