Cannabinoids in Cancer: Molecular Mechanisms of Tumor Cell Death and Translational Opportunities

Cannabinoids can attack cancer cells through far more than a single mechanism. This 2026 review describes how natural and synthetic cannabinoids can suppress tumor-cell growth, angiogenesis and metastasis while activating multiple forms of regulated cancer-cell death, including apoptosis, autophagy-dependent cell death, necroptosis, ferroptosis and parthanatos.

The researchers detail an interconnected network of molecular pathways affected by cannabinoids, including PI3K/AKT/mTOR, MAPK/ERK, NF-κB, TRIB3/AKT/mTORC1 and ceramide/ROS signaling. These pathways control whether cancer cells survive, proliferate, respond to stress or undergo programmed destruction, giving cannabinoids multiple potential points of attack against malignant cells.

The review also finds that cannabinoids may enhance conventional anticancer treatments by engaging complementary cell-death pathways. The authors conclude that cannabinoids represent promising anticancer agents and therapeutic adjuvants, with much of the direct anticancer evidence still coming from preclinical research and clinical translation now depending on better dosing, formulations and controlled human studies.

“Cannabinoids are terpenophenolic compounds derived from Cannabis sativa L. that exert a broad range of biological and pharmacological activities. Increasing evidence highlights their potential as modulators of cancer progression specifically through the suppression of tumor cell growth, angiogenesis, and metastasis across multiple tumor models.

This review provides a comprehensive overview of the molecular mechanisms by which natural and synthetic cannabinoids induce regulated cancer cell death.

Current evidence demonstrates that cannabinoids regulate multiple forms of cancer cell death, including apoptosis, autophagy-dependent cell death, necroptosis, ferroptosis, and parthanatos. These effects are mediated through complex and interconnected signaling pathways such as TRIB3/AKT/mTORC1, PI3K/AKT/mTOR, MAPK/ERK, NF-κB, ERK/JNK/p38-MAPK, and ceramide/Raf1/ERK/ROS.

In addition to their direct antitumor effects, cannabinoids can enhance the efficacy of conventional anticancer therapies through the coordinated regulation of complementary cell death pathways. They also provide clinically relevant supportive benefits in palliative care, alleviating chemotherapy-induced nausea, cachexia, and mood or sleep disturbances.

Collectively, these findings identify cannabinoids as promising anticancer agents and therapeutic adjuvants, predominantly in the preclinical setting. However, significant challenges remain regarding their safety, optimal dosing, formulation, and clinical efficacy. Further mechanistic studies, rigorous preclinical research, and well-designed clinical trials are required to establish the translation of cannabinoid-based therapies into precision oncology.”

https://pubmed.ncbi.nlm.nih.gov/42793092

“The cannabis plant, a member of the Cannabaceae family, has been traditionally utilized for centuries for spiritual and remedial healing.”

“The anticancer activity of cannabinoids was discovered in 1975 by Munson et al.. Cannabinoids suppress cancer cell proliferation, angiogenesis, tumor invasion, metastasis, and stemness while inducing different modes of cell death pathways.”

“In summary, this review highlights the growing body of evidence supporting the ability of cannabinoids to induce multiple forms of cell death across a broad spectrum of cancer types. Through the modulation of diverse molecular and signaling pathways, cannabinoids have emerged as promising anticancer agents, mostly in preclinical models, with the potential to target tumor growth, survival, and progression, ultimately triggering diverse cell death mechanisms.”

https://www.mdpi.com/2218-273X/16/9/1260

An Examination of the Anti-Cancer Properties of Plant Cannabinoids in Preclinical Models of Mesothelioma

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“Mesothelioma is an aggressive cancer with limited treatment options and a poor prognosis. Phytocannabinoids possess anti-tumour and palliative properties in multiple cancers, however their effects in mesothelioma are unknown. We investigated the anti-cancer effects and potential mechanisms of action for several phytocannabinoids in mesothelioma cell lines.

A panel of 13 phytocannabinoids inhibited growth of human (MSTO and H2452) and rat (II-45) mesothelioma cells in vitro, and cannabidiol (CBD) and cannabigerol (CBG) were the most potent compounds. Treatment with CBD or CBG resulted in G0/G1 arrest, delayed entry into S phase and induced apoptosis. CBD and CBG also significantly reduced mesothelioma cell migration and invasion. These effects were supported by changes in the expression of genes associated with the cell cycle, proliferation, and cell movement following CBD or CBG treatment. Gene expression levels of CNR1, GPR55, and 5HT1A also increased with CBD or CBG treatment. However, treatment with CBD or CBG in a syngeneic orthotopic rat mesothelioma model was unable to increase survival.

Our data show that cannabinoids have anti-cancer effects on mesothelioma cells in vitro and alternatives of drug delivery may be needed to enhance their effects in vivo.”

https://pubmed.ncbi.nlm.nih.gov/35954477/

We showed that several phytocannabinoids inhibited growth of mesothelioma cells, with two phytocannabinoids, cannabidiol (CBD) and cannabigerol (CBG), being the most potent. CBD and CBG also inhibited mesothelioma cell migration and invasion. Gene expression analysis highlighted signalling pathways that play a role in how CBD and CBG may exert their anti-cancer effects. CBD and CBG were unable to increase survival in a rat model of mesothelioma but this may be due to limitations in the drug delivery method.

Our data present the first report that plant cannabinoids have anti-proliferative effects on mesothelioma cells, that was associated with apoptosis, rather than autophagy or production of ROS. CBD and CBG were the most potent cannabinoids and also inhibited mesothelioma cell migration and invasion.”

https://www.mdpi.com/2072-6694/14/15/3813/htm

Long-term benefit from immune modulation and anti-inflammatory treatment in metastatic mesothelioma.

Respiratory Medicine Case Reports“A 64 year old male heating engineer was investigated for a persistent cough and found to have epithelioid mesothelioma with pleural effusion, lung nodules and increased thoracic lymph nodes. He declined standard of care treatment following his own research and he was enrolled in a named patient programme of IMM-101. He was advised to correct his low vitamin D3 level and to start using anti-inflammatories such as aspirin, bromelain and low dose Naltrexone. At review one year later a CT scan showed no change and he continued on the regimen. Four years after the diagnosis a CT scan showed that there was a modest but definite progression of the left malignant pleural thickening, and a new right-sided effusion, enlargement of several intrathoracic nodes which had been noted on the early scans. The chest wall lump eventually broke down and required local radiotherapy. He then developed abdominal pain and found to have peritoneal disease. Last year he obtained the cannabinoids CBD and THC which slowed down the disease and a CT scan after he had been on this for six months, showed that his disease was fairly stable with marginal progression.”

https://www.ncbi.nlm.nih.gov/pubmed/31788420

“The patient gave his full written consent for this report and is keen that others can benefit from this treatment.”

https://www.sciencedirect.com/science/article/pii/S2213007119303168?via%3Dihub