Four days of THC may make breast cancer less aggressive, according to a new study

A new study published in Communications Biology highlights the role of the CB2 cannabinoid receptor in the breast cancer.

Rather than simply trying to destroy tumor cells, researchers have discovered that a temporary modification of CB2 receptor signaling can steer cancer cells toward a more differentiated and less plastic state, which could reduce their ability to invade tissues, regenerate, and form metastases.

These results are still in the preclinical stage and are derived primarily from three-dimensional tumor organoids and experiments in mice, supplemented by additional experiments using organoids derived from human breast tumors.

Targeting Cancer's Ability to Change Its Identity

One of the obstacles to cancer treatment is the cellular plasticity : Tumor cells can alter their biological state, particularly by acquiring stem cell-like characteristics associated with resistance and metastatic progression. The researchers sought to determine whether the endocannabinoid system, and in particular the CB2 receptor, might influence this process.

Their experiments involved breast tumor organoids exposed for four days to a very low concentration (10 nanomolar) of THC, followed by a period without cannabinoids.

Instead of producing the cytotoxic effect associated with much higher concentrations, this brief exposure led to persistent changes. The organoids evolved into a luminal-type phenotype and exhibited reduced collective migration, fewer stem-like properties, and a diminished capacity for self-renewal. Preliminary experiments conducted on breast cancer organoids derived from patients produced comparable phenotypic changes.

This distinction is important: the proposed strategy is not primarily about destroying cancer cells using cannabinoids. Rather, it is about limiting their ability to transition from one cellular state to another.

CB2 appears to be the key cannabinoid receptor

Experiments suggest that the CB2, rather than the CB1, The receptor most closely associated with the psychoactive effects of cannabis plays a central role.

The researchers tested several cannabinoid compounds and synthetic ligands. In particular, the SR2, a CB2-targeted inverse agonist, reproduced the main effects observed with THC, including reduced migration and self-renewal. The results suggest that disrupting the receptor’s baseline signaling may be more important than simply activating it.

The cellular changes also proved to be exceptionally long-lasting. After THC-pretreated organoids were transplanted into mice, they exhibited a reduced ability to initiate tumors and slower tumor growth. In another experiment involving mice, the pretreated cells generated significantly fewer pulmonary micro- and macro-metastases.

The study establishes a link between this persistence and transcriptional and epigenetic remodeling, suggesting that temporary modulation of CB2R might leave a more lasting biological imprint on the identity of tumor cells.

A Possible Link to Tamoxifen

Another potentially significant finding concerns the tamoxifen, a standard endocrine therapy for hormone-sensitive breast cancer.

Modulation of CB2 increased estrogen receptor signaling and shifted the organoids toward a state that appeared more responsive to endocrine therapy. When the researchers first exposed the organoids to THC or SR2 and then administered tamoxifen, sensitivity to the drug increased at several of the concentrations tested. The formation of resistant colonies was also reduced compared to treatment with tamoxifen alone.

Experiments conducted on tumor organoids derived from patients also revealed reduced motility and self-renewal capacity following this sequential approach, providing initial evidence that this phenomenon is not limited to a single mouse model of cancer.

Promising biology, but not a cannabis-based cancer treatment

These results open up an intriguing line of research regarding the CB2 receptor and breast cancer, but there remains a considerable gap between these experiments and a treatment intended for patients.

It is important to note that the researchers describe a gradual stabilization toward a luminal-like state, not a complete transformation of malignant cells into differentiated normal cells. They suggest that relatively minor changes in CB2R signaling can trigger broader, self-perpetuating changes in tumor behavior.

For now, this research provides a mechanistic hypothesis rather than clinical evidence that the consumption of Cannabis or THC may prevent or treat breast cancer. Further research will be needed to determine whether targeting CB2R can be safely and effectively translated into treatments for humans.

A study published in Communications Biology explores a still little-known role of the CB2 cannabinoid receptor in the breast cancer.

The researchers did not investigate whether cannabinoids could directly destroy cancer cells. Instead, they explored another avenue: Is it possible to make these cells less capable of changing and adapting?

After just four days of exposure to a very low dose of THC, tumor cells cultured in the laboratory developed characteristics associated with a less aggressive state. Even more surprising, some of these changes persisted long after exposure had ceased.

However, these results are preclinical. They are primarily derived from organoids—miniature tumor models grown in the laboratory—and from experiments in mice. Organoids derived from human tumors have also been studied, but these studies do not allow us to conclude that the treatment is effective in patients.

Preventing Cancer Cells from Changing Their Behavior

Cancer cells have a particularly problematic ability: they can change state to adapt to their environment. This phenomenon, known as cellular plasticity, can, in particular, enable them to acquire characteristics similar to those of stem cells, enhancing their resistance and their ability to proliferate.

The researchers wanted to find out whether the endocannabinoid system, and more specifically the CB2 receptor, could play a role in this mechanism.

They exposed breast tumor organoids for four days to just 10 nanomolar of THC, a very low concentration.

The results differ from those typically sought with high concentrations of cannabinoids, which are intended to kill tumor cells. In this case, the cells were not simply destroyed: their behavior has changed.

They migrated less, exhibited fewer characteristics associated with stem cells, and had more difficulty renewing themselves. They also evolved into what scientists call a “luminal-like” state”, in other words, a more differentiated and stable state.

The potential goal, therefore, would be less about directly killing cancer cells than about reduce their ability to adapt and become more aggressive.

Why Researchers Are Interested in the CB2 Receptor

The experiments primarily refer to the CB2, rather than the CB1, as the person responsible for these changes.

To test this, the scientists used several molecules that target these receptors. The SR2, a synthetic molecule that acts on CB2, produced effects similar to those of THC: the cells migrated less, and their ability to regenerate decreased.

However, the mechanism appears to be more complex than simply activating CB2. Researchers believe that it is the disruption of the receptor's normal activity which could drive the cells toward this more stable state.

And the effects didn't disappear right away.

When organoids that had previously been exposed to THC were implanted in mice, tumors appeared later and progressed more slowly. In another experiment, the researchers also observed fewer lung metastases in animals that received the pretreated cells.

At the same time, the researchers observed changes in gene activity and chromatin organization. These changes may help explain why the effect persists after the cannabinoid has been cleared from the system.

Cells that are more sensitive to tamoxifen?

The study also presents an interesting finding regarding the tamoxifen, a drug used to treat certain hormone-sensitive breast cancers.

After CB2 modulation, the cells exhibited more characteristics associated with the estrogen response. The researchers therefore tested a two-step approach: four days of THC or SR2, a period without these molecules, followed by tamoxifen.

The organoids prepared in this way proved to be more sensitive to tamoxifen than those treated with the drug alone. The researchers also observed fewer resistant colonies.

Experiments conducted using organoids derived from patients' tumors yielded similar results, including a reduction in their mobility and their ability to regenerate.

Not a cancer treatment just yet

These results do not mean that THC or cannabis is a treatment for breast cancer.

The study was conducted primarily using cell and animal models. Therefore, it does not show that cannabis use would have the same effects in humans, nor that it could prevent or treat cancer.

The value of this research lies elsewhere: it identifies CB2 as a Potential Target for Regulating Cancer Cell Plasticity. Rather than focusing solely on eliminating tumor cells, future treatments might eventually aim to keep them in a state where they have a harder time progressing, resisting drugs, and spreading.

The four days of THC therefore consist mainly of the following here an experimental tool for elucidating the role of CB2, rather than a treatment protocol. The next step will be to determine whether this mechanism can actually be safely applied in humans.