Background: Cannabidiol (CBD), a major non-psychoactive phytocannabinoid derived from Cannabis sativa, has attracted increasing attention as a potential anticancer agent because of its pleiotropic biological activities and favorable safety profile. However, the mechanisms by which CBD regulates tumor cell death and their therapeutic relevance remain incompletely understood. Methods and Results: This review summarizes current evidence on the molecular mechanisms by which CBD regulates tumor cell death across different cancer models. Available studies indicate that CBD exerts antitumor effects through multi-target and multi-pathway mechanisms involving oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, calcium homeostasis imbalance, and modulation of signaling networks such as PI3K/Akt/mTOR, MAPK, NF-κB, and PPARγ. Through these interconnected processes, CBD can induce apoptosis, autophagy, ferroptosis, pyroptosis, and cell cycle arrest in a context-dependent manner. Notably, CBD may activate multiple regulated cell death pathways simultaneously or sequentially within the same tumor model, reflecting a broader stress-response network rather than a single cytotoxic mechanism. Therapeutic Implications: By coordinately engaging multiple cell death pathways and modulating the tumor microenvironment, CBD provides mechanistic insights and potential opportunities for the development of novel anticancer strategies. However, current evidence remains predominantly preclinical, while challenges related to oral bioavailability, pharmacokinetic variability, dose optimization, and potential drug interactions continue to limit translational progress. Conclusion: Collectively, available evidence suggests that CBD functions as a pleiotropic modulator of tumor cell fate rather than a classical single-target cytotoxic agent. Further mechanistic, pharmacological, and clinical studies are required to support the rational development of CBD-based anticancer therapies. Keywords: cannabidiol, tumor cell death, signaling pathways, antitumor therapy
Wang et al. (Fri,) studied this question.