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  • Writer's pictureTravis Cesarone

Endocannabinoid system feedback in a tumour microenvironment

Updated: Feb 8, 2023

Cannabis’s primary ingredients target the endocannabinoid system, which regulates mechanisms throughout the entire body and brain. Explained in simple terms, tumours and cancers are unorthodox growths of cells. And the tumour microenvironment, consisting of an endocannabinoid system, unfortunately, hijacks the immune system.

Medicines must be personalized and designed based on each type of cancer. Nestled within a matrix of mechanisms known as a microenvironment, cancerous tissues entangle themselves in protective immune cells.

Similar to cancer, tumors are growths of abnormal tissues surrounded by a microenvironment. They can be benign (non-cancerous) or malignant (cancerous). Benign tumors are not life-threatening, whereas malignant growths can be life-threatening if left untreated. (1)

Cannabinoids and cancer selectivity

Cannabis consists of cannabinoids that activate when cooked or smoked, such as tetrahydrocannabinolic acid (THCa.) Cannabinoid activation is a chemical process known as decarboxylation that leaves behind CO2 and D9-THC. Activity, in this case, depicts intoxicating effects that depend on CB1 receptors within the CNS, especially the hippocamp.

A study assessing glioblastoma cells discovered that THC and CB1 receptors did not kill brain cancer cells collected from human patients. CBG and CBD, on the other hand, targeted glioblastoma through two targets. CBD and CBG are antagonists to GRP55 — the purported third cannabinoid receptor. Secondly, CBD, more than CBG, deactivates TRPV1 channels.

GPR55 and TRPV1 deactivation independently turn down calcium currents. While CB1 receptor activation by THC separately turns down calcium currents. THC still has biphasic effects on tumour and cancer-protecting immune cells in the microenvironment, despite its ability to also turn down calcium currents. (2)

A tumour’s microenvironment

Tumours surround themselves in a microenvironment of various mechanisms, blood vessels, and immune cells. Natural killers, T, B, and other immune cells attack tumours. At the same, tumours induce extracellular signals that facilitate immune tolerance.

Within the microenvironment, endocannabinoids and their associated ligands positively and negatively engage tumours and cancerous tissues. Phytocannabinoids introduced into the environment from an exogenous source, such as cannabis, can also interfere with the microenvironment. At the same time, cannabinoids can promote cancer progression and immune evasion.

How cancer evades the immune system

Cancer uses four different immune cells to protect itself. Genetics, alongside the characteristics and location of each type of cancer, can impact immune cells in the microenvironment known as don’t eat me signals, according to Professor Irv Weissman.

Earning his degree as a medical doctor while studying at Stanford University in 1965, Weismann recently discovered and developed an antibody that inhibits an anti-tumor suppressor known as CD47. He also elucidated CD24 as an evasion cell, but cancers defend themselves with two other cells. (3)

Notably, macrophages comprise several components, including well-adjusted cannabinoid receptors, to help regulate cellular function. At the same time, studies suggest chronic THC consumption can unbalance macrophage polarity. as an evasion cell, but cancers defend themselves with two other cells. 

Attached to some CD4 T cells is a genetic factor — Foxhead Box Protein 3 (FoxP3.) Genetic factors code for proteins, enzymes, and various ligands. FoxP3 codes, in part, for a defence signal known as Programmed Cell Death Factor 1 (PD1.) THC has positive or negative impacts on FoxP3, given the existence of an injury. (4)

THC and anti-tumor suppression

During injury, orthostatic CB1 receptor agonists induce the transcription factor known as FoxP3. This would mean that THC protects cancer from the immune system. But tissues exposed to THC express a generally more acute T cell environment, balancing the impact on evasive and offensive cancer signals. (5)

Endocannabinoid system components, including 2-AG, PEA, and OEA, play a role in macrophage immunity. Macrophages are critical cells to launch an efficient attack against cancer. While it depends on every case, defense signals often cannot protect against cancer when macrophages disproportionately polarize.

Notably, macrophages comprise several components, including well-adjusted cannabinoid receptors, to help regulate cellular function. At the same time, studies suggest chronic THC consumption can unbalance macrophage polarity. (6)

FoxP2 and cannabis seeking are correlated, yet the cause is unknown. However, FoxP2 induces P21 proteins, which reduce tonic endocannabinoid signalling. Conversely, inhibition of protein kinase MAPK induces FoxP2. And CB1 receptor activity has biphasic effects on MAPK, completing the feedback loop.

Do transcription factors cause cannabis seeking?

THC’s biphasic effect on transcription factors is a give and take. A study published in the Lancet’s Journal of Psychiatry suggests that a Fox protein family member involved in speech and oncogenesis called FoxP2 causes cannabis use syndrome. Cannabinoid seeking can, however, occur as a result of endocannabinoid stunting. (6)

Unlike its neighbour, FoxP2 does not strongly associate with interleukins and cytokines. Instead, this transcription factor induces a protein that oddly knocks down cancer and endocannabinoid tone. A deep dive reveals that depleted endocannabinoid tone leads to compensatory cannabis-seeking behaviour. (7)

Scientists do not exactly know how FoxP2 affects endocannabinoid tone. However, the transcription factor boosts P21 proteins, which affect G Protein switches similar to those found in the cannabinoid one (CB1) receptor. FoxP2 might knock down endocannabinoid tone by limiting cannabinoid receptor expression. A proper answer does, however, require further research.

This author surmises that regulation of CB1 receptor-MAPK interactions via allosteric modulation of G-proteins is a potential therapeutic target in oncogenesis.


  1. Braile, M., Marcella, S., Marone, G., Galdiero, M. R., Varricchi, G., & Loffredo, S. (2021). The Interplay between the Immune and the Endocannabinoid Systems in Cancer. Cells, 10(6), 1282.

  2. Lah, T. T., Majc, B., Novak, M., Sušnik, A., Breznik, B., Porčnik, A., Bošnjak, R., Sadikov, A., Malavolta, M., Halilčević, S., Mlakar, J., & Zomer, R. (2022). The Cytotoxic Effects of Cannabidiol and Cannabigerol on Glioblastoma Stem Cells May Mostly Involve GPR55 and TRPV1 Signalling. Cancers, 14(23), 5918.

  3. Barkal, A.A., Brewer, R.E., Markovic, M. et al. CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature 572, 392–396 (2019).

  4. Gordon, S. R., Maute, R. L., Dulken, B. W., Hutter, G., George, B. M., McCracken, M. N., Gupta, R., Tsai, J. M., Sinha, R., Corey, D., Ring, A. M., Connolly, A. J., & Weissman, I. L. (2017). PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature, 545(7655), 495–499.

  5. Angelina, A., Pérez-Diego, M., López-Abente, J. et al. Cannabinoids induce functional Tregs by promoting tolerogenic DCs via autophagy and metabolic reprograming. Mucosal Immunol 15, 96–108 (2022).

  6. Staiano RI, Loffredo S, Borriello F, et al. Human lung-resident macrophages express CB1 and CB2 receptors whose activation inhibits the release of angiogenic and lymphangiogenic factors. J Leukoc Biol. 2016;99(4):531-540.

  7. Johnson, E. C., Demontis, D., Thorgeirsson, T. E., Walters, R. K., Polimanti, R., Hatoum, A. S., Sanchez-Roige, S., Paul, S. E., Wendt, F. R., Clarke, T. K., Lai, D., Reginsson, G. W., Zhou, H., He, J., Baranger, D. A. A., Gudbjartsson, D. F., Wedow, R., Adkins, D. E., Adkins, A. E., Alexander, J., … Agrawal, A. (2020). A large-scale genome-wide association study meta-analysis of cannabis use disorder. The lancet. Psychiatry7(12), 1032–1045.

  8. Xia S, Zhou Z, Leung C, et al. p21-activated kinase 1 restricts tonic endocannabinoid signaling in the hippocampus. Elife. 2016;5:e14653. Published 2016 Jun 14. doi:10.7554/eLife.14653

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