Cannabidiol enhances etoposide efficacy in non-small cell lung cancer by engaging a p53-mTOR-TFEB lysosomal death program

The search for more effective and safer cancer therapies has intensified interest in combination regimens that repurpose well-established agents. Here, we investigated whether cannabidiol (CBD), a cannabis-derived compound clinically used for pediatric epilepsy, can potentiate the anticancer activity of etoposide in non-small cell lung cancer (NSCLC). Among multiple chemotherapeutics tested, etoposide displayed the most pronounced reduction in NSCLC cell viability when combined with CBD, indicating a robust synergistic interaction. To elucidate the underlying mechanisms, we performed comprehensive transcriptomic and proteomic profiling, revealing that the CBD-etoposide combination up-regulated gene programs associated with autophagic cell death while concomitantly downregulating key oncogenic drivers linked to tumor progression. Mechanistically, this autophagic cell death was associated with PI3K-AKT-mTOR pathway inactivation and required functional p53. Importantly, downstream of mTOR suppression, the combination was associated with reduced TFEB phosphorylation, enhanced TFEB nuclear translocation, and increased transcriptional activation of lysosome-related gene networks, consistent with amplification of lysosomal stress programs that can contribute to lysosome-associated cell death. Notably, the therapeutic synergy was independent of classical cannabinoid receptors and transient receptor potential channels, supporting a noncanonical mode of CBD action. We also performed pharmacological blockade experiments using antagonists of PPARgamma and GPR55 to test whether these pathways contribute to the CBD-etoposide response. Collectively, our findings suggest that CBD combined with etoposide represents a promising strategy to enhance treatment efficacy in NSCLC-particularly in tumors retaining p53 function-by concurrently engaging autophagic/lysosomal cell death programs and suppressing oncogenic signaling beyond canonical cannabinoid pathways.