Gamma Delta T-Cell: A Double-Edged Sword for Cancer

Illustration of human cancer cells.

The Marvel of the Immune System

Every day, over a trillion of cells in your body fight to keep you safe (Sender et al., 2023). They work in harmony with each other to win countless battles, all while you go about your day as normal. To accomplish this, immune cells have evolved to wield tremendous power. Some can cause widespread inflammation, and others can even command other cells to destroy themselves. Luckily, our immunity has evolved countless safety measures to prevent these functions from being used on our healthy cells. However, in certain situations, our immune system may cause more harm than good.

The gamma delta (γδ) T-Cell is unique from other immune cells through several ways. To start, T-Cells have a specialized receptor called the T-Cell Receptor (TCR). Most commonly, the TCR is formed of alpha and beta chains. However, the TCRs of γδ T-Cells are made of gamma and delta chains. The receptor's unique constitution allows it to recognize certain molecules that are often secreted by bacteria and cancerous cells, making it an important asset in our body's arsenal (Kabelitz, 2020).

Illustration of T-Cells attaching to a cell.

How Gamma Delta T-Cells Fight Cancer

When a tumour grows, certain pathways within the cancerous cell begin to malfunction. One such example is the Mevalonate pathway, which is used by our cells to synthesize cholesterol (Hashemi et al., 2017). When the Mevalonate pathway is interrupted, the backlog of metabolites known as “phosphoantigens” can be detected by certain subsets of gamma delta TCRs without being presented to it by another immune cell (Kabelitz, 2020). Once a gamma delta T-Cell is activated, it can then order the cancerous cell’s death by using cytotoxic agents. They also release inflammatory molecules known as cytokines to ramp up the immune response (Hayati et al., 2026).

These subsets of gamma delta T-Cell are particularly good at tumour suppression. However, other subsets seem to have the opposite effect.

How Gamma Delta T-Cells Help Cancer Grow

In certain contexts, subtypes gamma delta T-Cells release a cytokine called IL-17. IL-17 is a pro-inflammatory cytokine whose job is mainly to recruit neutrophils to a site of infection or injury (Zenobia & Hajishengallis, 2015).

Certain subsets of gamma delta T-Cells, particularly IL-17 secreting Vδ1 T-Cells, are correlated with negative patient outcomes in colorectal cancer (CRC) patients. CRC is not the only type of cancer where this has been observed. The details of how IL-17 causes this are complex and vary between each type of cancer, but one possible mechanism involves IL-17 recruiting myeloid-derived suppressor cells which suppress the activation of natural killer and cytotoxic T-cells (Wang et al., 2022).

Interestingly though, IL-17 appears to exhibit tumour-suppressing effects in other types of cancer, such as gastric and ovarian cancer. In these cases, IL-17 recruits cytotoxic T-Cells who are further enhanced by IL-12 signals secreted by macrophages (Wang et al., 2022).

Illustration of CAR T-Cell therapy.

Impact on Immunotherapy

The double-edged sword of gamma delta T-Cells poses a challenge for application in immunotherapy. CAR-γδ T-Cell therapy involves scientists engineering specific receptors on γδ T-Cells to target cancer cells. However, its main problem lies in its toxicity (Hayati et al., 2026).

To address its main issues, scientists have trialed administering immune checkpoint inhibitors (ICI) alongside CAR-γδ T-Cell therapy. The addition of ICIs help combat the immune suppressive effects that can sometimes arise because of γδ T-Cells. If successful, it can help restore the full ability of immune cells to fight the cancer (Hayati et al., 2026). This approach to CAR-γδ T-Cell therapy shows immense promise.

Illustration of gamma delta T-Cells and a cancer cell.

Summary and Conclusion

Our immune system wields immense power, but things don’t always go to plan. Sometimes it tries to help and succeeds. Other times, it fails and makes things worse. Gamma delta T-Cells are extremely effective at detecting and killing cancer cells. But certain subsets release IL-17, and depending on the type of cancer, that can make things worse. This dual role poses challenges in their application in immunotherapy, but scientists haven’t given up. By administering immune checkpoint inhibitors, the immune suppressive signals can be negated. These applications prove the promising future of gamma delta T-Cells in immunotherapy, despite their double identity.

Gamma delta T-Cells might be a double-edged sword, but with an innovative solution, harnessing their immense tumour fighting ability would be a massive asset in the world of cancer immunotherapy. In fact, studies have already been conducted attempting to mitigate the risks, and the future is looking bright.

References

Gober, H.-J., Kistowska, M., Angman, L., Jenö, P., Mori, L., & De Libero, G. (2003). Human T Cell Receptor γδ Cells Recognize Endogenous Mevalonate Metabolites in Tumor Cells. The Journal of Experimental Medicine, 197(2), 163–168. https://doi.org/10.1084/jem.20021500

Hashemi, M., Hoshyar, R., Ande, S., Chen, Q. M., Solomon, C., Zuse, A., & Naderi, M. (2017). Mevalonate Cascade and its Regulation in Cholesterol Metabolism in Different Tissues in Health and Disease. Current Molecular Pharmacology, 10(1), 13–26. https://doi.org/10.2174/1874467209666160112123746

Hayati, M. J., Yaghmoorian Khojini, J., Khara, F., Heydari, A., Vousooghi, N., Abootorabi, S. M. S., Barkhordar, M., & Mousavi, M. J. (2026). Gamma Delta T Cells in the Tumour Microenvironment: A Double‐Edged Sword. Immunology, 177(1), 44–58. https://doi.org/10.1111/imm.70035

Kabelitz, D. (2020). Gamma Delta T Cells (γδ T Cells) in Health and Disease: In Memory of Professor Wendy Havran. Cells, 9(12), 2564. https://doi.org/10.3390/cells9122564

Sender, R., Weiss, Y., Navon, Y., Milo, I., Azulay, N., Keren, L., Fuchs, S., Ben-Zvi, D., Noor, E., & Milo, R. (2023). The total mass, number, and distribution of immune cells in the human body. Proceedings of the National Academy of Sciences, 120(44). https://doi.org/10.1073/pnas.2308511120

Wang, Y., Xu, Y., Chen, H., Zhang, J., & He, W. (2022). Novel insights based on the plasticity of γδ T cells in the tumor microenvironment. Exploration of Immunology, 98–132. https://doi.org/10.37349/ei.2022.00039

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Zenobia, C., & Hajishengallis, G. (2015). Basic biology and role of interleukin‐17 in immunity and inflammation. Periodontology 2000, 69(1), 142–159. https://doi.org/10.1111/prd.12083

Assessed and Endorsed by the MedReport Medical Review Board