Boosting Cancer-Fighting Immune Cells with IL-15 Gene Discovery

A newly discovered genetic switch may allow scientists to dramatically amplify the cancer-killing power of natural immune cells by harnessing the body’s own signaling molecules.

Researchers have uncovered a new way to enhance the cancer-fighting ability of the immune system. All people naturally produce a growth factor known as IL-15 that plays an essential role in protecting the body from cancer. This molecule helps stimulate the production and activity of immune cells that can quickly detect and destroy cancer cells when they first arise. Among these defenders are Natural Killer (NK) cells, which specialize in identifying and eliminating abnormal cells.

How Cancer Evades the Immune System

Cancer, however, has many ways to evade this defense system. Tumor cells can develop mechanisms that suppress immune cells such as NK cells, even when the tumors themselves produce the immune-stimulating factor IL-15. The cancer often overpowers the immune response.

One strategy has been to treat patients with drugs that activate the IL-15 receptor on immune cells. In theory, this approach should strengthen the body’s ability to attack tumors. In practice, these drugs have proven too toxic as they stimulate immune cells throughout the entire body instead of only within tumors, leading to serious side effects.

Discovery of a Gene to Boost Immune Sensitivity

Researchers at Monash University and oNKo-Innate in Melbourne, Australia have identified a gene that can be switched off in NK cells to make them far more responsive to the body’s own IL-15. This discovery opens the possibility of developing a new type of cancer therapy that enhances natural immune signals instead of overwhelming the system with drugs.

The study, led by Professor Nick Huntington of the Monash Biomedicine Discovery Institute, along with scientists from oNKo-Innate, was published in the international cancer journal Cancer Cell [1]. The researchers showed that disabling this gene in human NK cells greatly increased their responsiveness to very small amounts of IL-15, resulting in stronger anticancer activity and slowed the growth of colorectal cancer in preclinical models.

The gene identified produces an enzyme, which is significant because enzymes can often be targeted with small-molecule drugs. A medication that blocks this molecular pathway, along with several others, has already been tested in patients with myelodysplastic syndrome to trigger cancer cell death.

“Which gives us some confidence that more specific inhibitors can be discovered with improved safety profiles to be tested in settings where immunotherapy is sub-optimal and additional ways to enhance the immune response to cancer are needed,” Professor Huntington said.

Why Colorectal Cancer May Benefit

In patients with colorectal cancer, tumor cells produce higher levels of IL-15 than most healthy tissues. However, cancer cells can too mutate the IL-15 gene in ways that weaken the immune response. These mutations are linked to tumor recurrence and poorer outcomes for patients.

Increasing the sensitivity of immune cells to the body’s own IL-15 could help trigger powerful immune activity exactly where IL-15 is present, such as in colorectal tumors, while sparing healthy organs where IL-15 levels remain very low.

To identify this mechanism, the researchers used CRISPR screening to search for genes that influence how immune cells respond to growth factors. Their analysis revealed two genes that can either be removed in cell-based therapies or blocked with small-molecule drugs, both of which improved the cancer-killing ability of NK cells.

Professor Huntington also noted that this strategy could complement existing immunotherapies, potentially working alongside widely used cancer immune checkpoint inhibitors to strengthen the overall immune attack against tumors. “As such, drugs that target IL-15 signaling pathways could be logically combined for additive anti-cancer immune activity in advanced tumors,” he said.

Reference: Nikolic, I., Cursons, J., Shields, B., Chappaz, S., Sudholz, H., Meng, X., Constantinescu, P., Vijayakumaran, R., D’Angelo, M., Foroutan, M., Ladd, D., Veldman, M., Glab, J., Procter, T., Park, H.-Y., Contet, J., Deuss, F., Wong, K., Sun, Y., Berry, R., Rautela, J., & Huntington, N. D. (2025). Enhancing anti-tumor immunity of natural killer cells through targeting IL-15R signaling. Cancer Cell, 38(6), 1032–1047.e6. https://doi.org/10.1016/j.ccell.2025.05.011