“Cannabidiol (CBD) is a nonpsychoactive cannabinoid with emerging anticancer and immunomodulatory properties; however, its systems-level mechanisms in tumor-associated immune cells remain incompletely defined.

Here, we investigated CBD in a melanoma-T cell coculture model using integrated transcriptomic and proteomic analyses.

At a subcytotoxic concentration (10 μM), CBD selectively induced apoptosis in melanoma while preserving T-cell viability and enhancing IL-2 secretion. RNA sequencing revealed coordinated activation of stress-adaptive, immune activation, and trafficking programs, including modulation of T-cell receptor signaling and cytokine networks.

Data-independent acquisition proteomics identified activation of eukaryotic initiation factor 2 (EIF2) signaling, a central node of the integrated stress response (ISR) linking redox and endoplasmic reticulum stress to translational control. Multiomics integration converged on immune cell trafficking as a consistent outcome, with upregulation of ICAM1, ITGB1, and associated adhesion-related proteins.

These findings suggest ISR-dependent translational reprogramming as a putative mechanistic axis by which CBD reshapes T-cell function in the melanoma microenvironment.

Our study provides pharmacological insight into how CBD modulates tumor-immune interactions and suggests potential utility as an adjunct immunomodulatory agent in melanoma.”

https://pubmed.ncbi.nlm.nih.gov/42396083

“Plant-derived redox-active metabolites have emerged as important modulators of these stress-adaptive pathways, acting through conserved molecular nodes that integrate oxidative stress with cellular signaling. Cannabidiol (CBD) is a nonpsychoactive phytochemical that has attracted growing attention as a redox-active compound with antioxidant, cytoprotective, and anticancer properties. Apart from its direct effects on tumor cells, CBD has been reported to modulate inflammatory signaling, oxidative stress responses, and cell death pathways, including ferroptosis.”

“In conclusion, this study provides a comprehensive multiomics characterization of CBD’s role in reshaping T-cell function within the melanoma microenvironment through redox- and stress-responsive mechanisms. Using a melanoma-T cell coculture system, we demonstrate that CBD selectively promotes melanoma cell death while inducing coordinated transcriptomic and proteomic remodeling in T cells.”

https://pubs.acs.org/doi/10.1021/acsomega.6c01965

“Ultraviolet A (UVA) radiation disrupts the redox balance of melanocytes and may lead to the development of melanoma, highlighting the need for new skin protection strategies.

This study assessed the effect of phytocannabinoids [cannabigerol (CBG), cannabidiol (CBD), and CBG + CBD] on redox homeostasis in control and UVA-exposed melanocytes and in melanoma cells (SK-Mel-5).

UVA radiation increased the activity of prooxidant enzymes in both melanocytes and SK-Mel-5 cells and, consequently, the level of reactive oxygen species (ROS) (approx. 2-fold). It also activated nuclear factor erythroid 2 (Nrf2), as reflected by increased expression of heme oxygenase 1 (HO-1) (melanocytes approx. 2-fold; SK-Mel-5 approx. 7-fold). Concomitantly, antioxidant mechanisms were impaired, as demonstrated by reduced superoxide dismutase (SOD1/SOD2) activity and impaired glutathione and thioredoxin function. These changes were accompanied by increased levels of oxidative damage markers (isoprostanes, 4-hydroxynonenal-4-HNE, and 4-HNE-protein adducts) (43-100%) and increased inflammatory signaling, including increased expression of nuclear factor kappa B (NF-κB) subunits (melanocytes: p52 ~2-fold, p65 ~75%; SK-Mel-5: ~4-4.5-fold) and tumor necrosis factor alpha (TNF-α; ~30%).

Phytocannabinoid treatment modulated these UVA-induced changes.

In SK-Mel-5 cells, phytocannabinoids normalized the activity of prooxidant enzymes and consequently reduced ROS levels (~30%). They also reduced Nrf2 activation and HO-1 expression; however, CBG increased HO-1 level in melanocytes (~25-40%). Furthermore, phytocannabinoids enhanced antioxidant defense by increasing SOD activity, particularly in melanocytes (~10-40%), and restoring the glutathione and thioredoxin systems. Markers of oxidative damage were reduced by approximately 23-37% after treatment. Furthermore, phytocannabinoids attenuated NF-κB activation (p52 ~18-28%, p65 ~25-29% in melanocytes; ~20% in SK-Mel-5), while TNF-α levels remained unchanged. The effects in non-irradiated cells were modest (<15%).

These results suggest that phytocannabinoid-mediated modulation of redox balance may stabilize melanocytes exposed to UVA radiation and potentially reduce the risk of neoplastic transformation. However, the observed protective effects in SK-Mel-5 cells require further investigation and detailed molecular analysis.”

https://pubmed.ncbi.nlm.nih.gov/42351996

“The observed stabilizing effect of phytocannabinoids on the redox homeostasis of UVA-irradiated melanocytes is particularly relevant, as it may reduce conditions that favor neoplastic transformation.”

https://www.mdpi.com/2076-3921/15/6/690

“Melanoma represents one of the most aggressive forms of skin cancers, with advanced metastatic stages largely managed through chemotherapy. However, current therapeutic strategies remain limited by drug resistance and systemic toxicity. Cannabidiol (CBD), the primary nonpsychoactive constituent of Cannabis sativa, has recently attracted attention for its anticancer properties across multiple tumor types.

OBJECTIVES

This study aimed to explore the antitumor efficacy of CBD in melanoma and elucidate its underlying molecular mechanisms, with the goal of identifying novel therapeutic strategies to overcome resistance and reduce adverse effects associated with conventional treatments.

METHODS

The antiproliferative and pro-apoptotic effects of CBD were assessed in vitro using MTS, EdU, Transwell invasion, and flow cytometry. In vivo efficacy was evaluated using a murine lung metastasis model. Potential CBD targets in melanoma were identified through network pharmacology and molecular docking, with a focus on peroxisome proliferator-activated receptor γ (PPARγ) and validation by western blotting and immunofluorescence. Integrated transcriptomic and genome-wide methylation analyses were performed to investigate epigenetic modifications induced by CBD. Co-immunoprecipitation and chromatin immunoprecipitation assays were employed to detect the interaction between PPARγ and ten-eleven translocation 1 (TET1), including their binding to promoter regions of downstream factors. Methylation-regulated target genes were further validated using qPCR and MeDIP PCR.

RESULTS

CBD significantly induced apoptosis and inhibited cell proliferation and invasion of melanoma cells in vitro, while reducing pulmonary metastasis in vivo. Pharmacological and molecular docking analyses, supported by protein-level validation, identified PPARγ as a critical mediator of CBD activity. Transcriptomic and methylation analyses revealed that CBD modulated global DNA methylation patterns, partly through the formation of a PPARγ-TET1 complex. This complex regulated the demethylation of leucine-rich repeat and sterile alpha motif-containing 1 (LRSAM1), a newly identified anticancer gene whose upregulation markedly enhanced melanoma cell apoptosis and suppressed proliferation.

CONCLUSIONS

CBD exhibited strong antitumor activity in melanoma by modulating the PPARγ–TET1 complex to induce demethylation of LRSAM1, thereby suppressing tumor progression. These findings identify CBD as a promising candidate for melanoma therapy.”

https://www.sciencedirect.com/science/article/abs/pii/S0944711326000127

“In summary, this study investigated molecular targets and mechanisms by which CBD suppresses melanoma progression, emphasizing its role in PPARγ activation and epigenetic regulation. These findings establish a mechanistic basis and provide candidate targets for future clinical application of CBD in melanoma treatment.”

“This study provides the first evidence that CBD inhibits melanoma progression by modulating gene methylation. The identification of LRSAM1 as a PPARγ-TET1-regulated tumor suppressor expands current understanding of epigenetic regulation in melanoma and highlights LRSAM1 as a viable therapeutic target.”

https://www.scilit.com/publications/50c9c0a6d08f7880cebb9c69a2c3fca7

“Despite the targeted- and immunotherapies used in the past decade, survival rate among patients with metastatic melanoma remains low, therefore, melanoma is responsible for the majority of skin cancer-related deaths.

The ongoing investigation of natural antitumor agents, the nonpsychoactive cannabinoid, cannabigerol (CBG) found in Cannabis sativa is emerging as a promising candidate. CBG offers a potential therapeutic role in the treatment of melanoma demonstrating cell growth inhibition in some tumors. Its low water solubility and bioavailability hinder the potential effectiveness. To address these challenges, a modified CBG, namely LE-127/2 was synthesized by Mannich-type reaction.

The aim was to investigate the effect of this novel compound on cell proliferation as well as the mechanism of cell death with a particular focus on autophagy and apoptosis.

Human cutan melanoma cell lines, WM35, A2058 and WM3000 were utilized for the present study. Cell proliferation of the cells after the treatment with LE-127/2, parent CBG or vemurafenib was assessed by Cell Titer Blue Assay. Cells were treated with a 1.25-80 µM of the above-mentioned compounds, and it was found that at 20 μM of all drugs showed a comparable effective inhibition of cell proliferation, however, vemurafenib and CBG proved to be more effective than LE-127/2. In addition, clonogenic cell survival assays were performed to examine the inhibitory effect of LE-127/2 on the colony formation ability of melanoma cell lines.

Cells treated with 20 µM of LE-127/2 for 14 days showed about a 50% suppression of clonogenic cell survival. LE-127/2 exerted the most intensive inhibition on A2058 cell colonies. Furthermore, notably, LDH cytotoxicity assay performed on HaCaT cell line, proved LE-127/2 to be cytotoxic only at higher concentration, such as 80 μM, while the parent CBG was cytotoxic at concentration as low as 5 μM, suggesting that the new CBG derivative as a drug candidate may be applied in human pharmacotherapy without causing a substantial damage in intact epidermal cells. Analysis of protein expression revealed the impact of LE-127/2 on the expression of basic proteins (LC-3, Beclin-1 and p62) involved in the process of autophagy in the three different melanoma cell lines studied. Elevated expression of these proteins was detected as a result of LE-127/2 (20 µM) treatment. LE-127/2 also induced the expression of some proteins involved in apoptosis, and it is particularly noteworthy the increased level of cleaved PARP.

Based on the results obtained, it can be concluded that LE-127/2 induced autophagy could lead to the inhibition of cell proliferation and death in melanoma cells.”

https://pubmed.ncbi.nlm.nih.gov/39357769/

https://www.sciencedirect.com/science/article/pii/S0928098724002331?via%3Dihub