Balanced scale representing GPR55 and CB1 receptors in colorectal cancer prevention.

Gut Instincts: How a Hidden Receptor Could Be Your Key to Colorectal Cancer Prevention

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Lena Kashyap in Health & Wellness November 2026 • 4 min read.

"Unlocking the Secrets of GPR55 and Cannabinoid Receptors in the Fight Against Colorectal Cancer"


Colorectal cancer (CRC) remains a major health challenge, demanding innovative approaches beyond traditional treatments. Recent studies highlight the crucial role of the tumor microenvironment – the complex ecosystem surrounding cancer cells – in CRC development and progression. Within this environment, inflammatory mediators, immune cells, and their receptors interact in ways that can either fuel or suppress tumor growth.

Among the key players in this intricate network are cannabinoid receptors, particularly CB1 and GPR55. While CB1 has been shown to have anti-tumor effects in the gut, the function of GPR55 has remained largely unclear. New research is shedding light on GPR55's role in promoting CRC and how it interacts with CB1, offering potential new avenues for prevention and treatment.

This article explores the groundbreaking findings that reveal the complex interplay between GPR55 and CB1 in colorectal cancer. Learn how these receptors influence tumor growth, inflammation, and the immune response, and what this could mean for the future of CRC prevention and therapy.

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The Current U.S. Burden

The CDC reports that colorectal cancer is the fourth most common cancer in U.S. men and women, excluding some types of skin cancer. It is also the fourth leading cause of cancer-related deaths in the United States, according to the CDC. The latest data cited by the CDC recorded 155,662 new colorectal cancer cases in 2023 and 54,468 deaths in 2024. The American Cancer Society National Colorectal Cancer Roundtable separately describes colorectal cancer as the second leading cause of cancer death when U.S. men and women are combined, indicating that rankings can differ by the measure and population used.

Screening Requires Choice

Colorectal cancer prevention and early diagnosis rely on identifying and addressing modifiable risk factors and on population screening. A 2024 review describes population screening as well established in clinical practice, while noting that evidence continues to increase. A review of programmatic screening strategies emphasizes that the optimal method can differ depending on the scenario. This means screening approaches must be considered in light of their respective advantages and limitations rather than treated as universally interchangeable.

The Surprising Role of GPR55: From Inflammation to Tumor Growth

Balanced scale representing GPR55 and CB1 receptors in colorectal cancer prevention.

The study published in the International Journal of Cancer uncovers a previously underappreciated role for GPR55 in promoting colorectal cancer. Researchers using mouse models discovered that GPR55 encourages tumor growth by altering the balance of immune cells within the tumor microenvironment. Specifically, GPR55 promotes the accumulation of myeloid-derived suppressor cells (MDSCs), which suppress the anti-tumor activity of T cells. It also modulates levels of key inflammatory mediators like COX-2 and STAT3, known to drive cancer progression.

In essence, GPR55 appears to create a microenvironment that favors tumor development. When GPR55 was removed, the researchers observed the opposite effect: increased numbers of cytotoxic T cells (immune cells that kill cancer cells) and reduced levels of tumor-promoting inflammatory molecules.

Here’s a quick breakdown of the key findings:
  • GPR55 promotes colorectal cancer growth in mouse models.
  • GPR55 influences the balance of immune cells in the tumor microenvironment.
  • GPR55 modulates inflammatory mediators known to drive cancer progression.
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GPR55 in Emerging Cancer Research

Recent reviews place GPR55 within broader research on the endocannabinoid system, cancer biology, and tumor environments. One review reports that GPR55 involvement in cancerogenesis has often been studied through its effects in cancer cells, while a 2024 pancreatic cancer study examined its role in the immune tumor microenvironment using GPR55 knockout mice. A separate review reports pro-tumor activity of these receptors in mouse models of colon carcinoma. These findings are research signals rather than proof that a GPR55-targeted prevention strategy is ready for clinical use in colorectal cancer.

An Unsettled Receptor

The role of GPR55 in gastrointestinal cancers remains unclear. The Crossref record for the colorectal cancer study notes that cannabinoid receptor 1 has been reported to suppress intestinal tumor growth, while GPR55's role in gastrointestinal cancer development is uncertain. A 2022 report investigated GPR55 messenger RNA expression in regional lymph nodes from colon cancer patients across TNM stages I through IV and compared them with non-cancerous disease controls. These observations underscore that expression and biological association do not by themselves establish a successful preventive treatment.

Agonists Versus Antagonists

GPR55 research uses both selective agonists and antagonists as experimental tools. A comparative guide to selective agonists, including ML-184 and alternatives, describes GPR55 as a potential target in cancer and other physiological or pathological conditions. A separate guide compares GPR55 antagonists for researchers and drug-development professionals. It focuses on available experimental data, including performance, selectivity, and the methods used to evaluate candidate compounds. These guides support comparison of research tools, not a conclusion that either class has been proven to prevent colorectal cancer.

Interestingly, when researchers tried to manipulate GPR55 directly in colon cancer cell lines, they didn't see any effect on cell proliferation. This suggests that GPR55's primary influence on CRC is through modulating the tumor microenvironment rather than directly affecting cancer cell growth.

Balancing the Gut: A New Frontier in CRC Prevention?

These findings open exciting new avenues for colorectal cancer prevention and treatment. Targeting GPR55 to modulate the tumor microenvironment could represent a novel therapeutic strategy. Furthermore, the discovery that CB1 and GPR55 have opposing roles highlights the potential of balancing the endocannabinoid system in the gut to prevent or slow CRC development. While further research is needed to fully understand the clinical implications, these findings offer a promising glimpse into the future of CRC therapy.

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Prognostic Investigation

A study investigated the prognostic value of GPR55 in colon cancer. It measured GPR55 messenger RNA expression in 382 regional lymph nodes from 121 colon cancer patients. The patients were observed for 12 years after curative surgery. This design provides a long-term clinical context for evaluating whether GPR55 expression is associated with outcomes, but the source description does not establish a prevention benefit.

Prevention in a Changing Landscape

A 2026 Nature roadmap states that early-onset colorectal cancer is rising globally. It identifies current knowledge gaps in risk factors and proposes an integrative conceptual model for discovering and preventing those risks. Other 2025 and 2026 editorials frame colorectal cancer prevention, diagnosis, and treatment as continuing areas for scientific discussion and future progress. Emerging genetic, epigenomic, and biomarker research is also described as expanding the potential for earlier diagnosis.

From Cell Lines to Disease

Research has described a proliferation-enhancing effect of GPR55 in several cancer cell lines. The PubMed-listed study specifically examined whether GPR55 signaling affected proliferation in colon cancer cell lines. It also notes that lysophosphatidylinositol was found at elevated levels in cancer patients. A separate report describes GPR55 as involved in physiological and pathological processes of the gastrointestinal tract and as tumor-promoting in various cancers, but these findings do not by themselves define its clinical role in colorectal cancer.

Evidence in Human Tissue

Human colorectal cancer tissue has shown differential epigenetic methylation of CNR1 and GPR55 compared with control samples. This finding places cannabinoid-receptor biology within measurable molecular differences in human disease. However, differential methylation alone does not show that GPR55 causes colorectal cancer or that changing its activity would prevent it. Further clinical research is needed to determine how such tissue-level findings relate to patient outcomes and prevention.

What mouse models can show about GPR55

Animal study (level 5 of 8)

The study used AOM- and DSS-driven colorectal cancer mouse models, so it can test how GPR55 relates to tumor development and immune-cell patterns in those models, but cannot by itself establish a preventive effect in people.[1]

The patient component was a cohort of 86 people with colorectal cancer. Differences in receptor messenger RNA expression in that group provide human observational context, not proof that either receptor caused the disease.[1]

What the opposing receptor roles suggest

Taken together, the mouse findings and the patient expression comparison point to different roles for GPR55 and CB1 in colon carcinogenesis: GPR55 appears tumor-promoting, while CB1 appears tumor-suppressive. This is a biological contrast, not evidence that changing either receptor prevents colorectal cancer in people.[1]

AOM/DSS mouse models and a colorectal cancer patient cohort

Study designAnimal study[1]
PopulationCRC mouse models and a cohort of CRC patients[1]
Sample size86 CRC patients[1]
Main outcomeRole of GPR55 in colorectal cancer development[1]
Times cited62[1]

How later work has placed the GPR55 findings

A later pancreatic cancer study describes earlier colorectal mouse work as finding smaller tumors and more T-cell infiltration, alongside fewer myeloid suppressor cells, after GPR55 knockout; it presents this as a possible T-cell-suppressive role for GPR55.[2]

Questions for follow-up studies

  • Do the different expression patterns in the patient cohort track with tumor characteristics or outcomes, rather than merely accompanying colorectal cancer?[1]

Terms used in the receptor study

GPR55
A putative cannabinoid receptor involved in physiological and pathological processes of the gastrointestinal tract.[1]

Sources

  1. G protein‐coupled receptor GPR55 promotes colorectal cancer and has opposing effects to cannabinoid receptor 1 (Wiley, 2017)
  2. GPR55 in the tumor microenvironment of pancreatic cancer controls tumorigenesis (2025)

About this Article -

Written with AI assistance from published research, and reviewed by the Mystum team. See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1002/ijc.31030, Alternate LINK

Title: G Protein-Coupled Receptor Gpr55 Promotes Colorectal Cancer And Has Opposing Effects To Cannabinoid Receptor 1

Subject: Cancer Research

Journal: International Journal of Cancer

Publisher: Wiley

Authors: Carina Hasenoehrl, David Feuersinger, Eva M Sturm, Thomas Bärnthaler, Ellen Heitzer, Ricarda Graf, Magdalena Grill, Martin Pichler, Stephan Beck, Lee Butcher, Dominique Thomas, Nerea Ferreirós, Rufina Schuligoi, Caroline Schweiger, Johannes Haybaeck, Rudolf Schicho

Published: 2017-09-21

Everything You Need To Know

1

What role does GPR55 play in colorectal cancer?

The study shows that GPR55 actively encourages the growth of colorectal cancer. This is achieved by influencing the environment around the tumor, specifically by increasing the presence of myeloid-derived suppressor cells (MDSCs), which hinder the function of T cells, vital for fighting cancer. Also, GPR55 alters the levels of inflammatory mediators like COX-2 and STAT3, substances known to accelerate cancer's progression. By manipulating the tumor microenvironment, GPR55 creates conditions favorable for the cancer to thrive. When researchers removed GPR55, they observed a shift towards an environment that suppressed tumor growth, with more cytotoxic T cells and reduced levels of tumor-promoting inflammatory molecules.

2

How do CB1 and GPR55 differ in relation to colorectal cancer?

CB1 and GPR55 are both types of cannabinoid receptors. CB1 has been found to have anti-tumor effects in the gut, working to potentially slow or prevent the growth of colorectal cancer. GPR55, conversely, has been shown to promote the progression of the cancer. The key difference is their function within the tumor microenvironment and how they interact with other elements of the immune system. The balance between these two receptors could be crucial in preventing or managing colorectal cancer.

3

Why is GPR55 considered important in the context of colorectal cancer?

GPR55's importance lies in its influence over the tumor microenvironment, a critical aspect of colorectal cancer development and progression. By manipulating the immune cells and inflammatory mediators in this environment, GPR55 can either support or hinder tumor growth. This makes GPR55 a potential target for therapeutic strategies, as modulating its activity could shift the balance towards an environment that suppresses tumor growth. The ability to target GPR55 offers a new perspective on how to prevent and treat colorectal cancer by focusing on the environment that supports the cancer's existence.

4

What are the implications of these findings on GPR55?

The implications of these findings are significant. They offer new potential avenues for the prevention and treatment of colorectal cancer by targeting GPR55. By understanding how GPR55 interacts with the tumor microenvironment and other receptors, researchers could develop strategies to modulate its activity. This approach could involve drugs or therapies that either block GPR55's function or enhance the activity of CB1, aiming to restore a healthy balance within the gut. The ultimate goal is to create an environment where tumor growth is suppressed, and the body's own immune defenses are strengthened.

5

What is the significance of the tumor microenvironment in colorectal cancer?

The tumor microenvironment is the complex ecosystem surrounding cancer cells, comprising immune cells, inflammatory mediators, and their receptors. This environment significantly influences colorectal cancer's development and progression. The interaction of these elements, especially the activity of receptors like GPR55 and CB1, determines whether the environment supports or suppresses tumor growth. Understanding and potentially manipulating this microenvironment is a key focus in developing new strategies for preventing and treating colorectal cancer, as it offers a way to directly impact the conditions that facilitate tumor development.

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