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 important 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 Cells, often called NK cells, which specialize in identifying and eliminating abnormal cells.
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. As a result, the cancer often overpowers the immune response.
One possible 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 because they stimulate immune cells throughout the entire body instead of only within tumors. This widespread activation can lead to serious side effects.
Until now.
Discovery of a Gene That Boosts 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 was led by Professor Nick Huntington of the Monash Biomedicine Discovery Institute, along with scientists from the Melbourne-based biotechnology company oNKo-Innate. Their findings were published in the international cancer journal Cancer Cell. The researchers showed that disabling this gene in human NK cells greatly increased their responsiveness to very small amounts of IL-15. As a result, the cells displayed stronger anticancer activity and slowed the growth of colorectal cancer in preclinical models.
The gene identified in the study produces an enzyme. This 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 in the body. However, cancer cells can also 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. At the same time, this approach may spare 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 strategies improved the cancer-killing ability of NK cells.
Professor Huntington also noted that this strategy could complement existing immunotherapies. According to him, the approach may work alongside widely used cancer immune checkpoint inhibitors to strengthen the overall immune attack against tumors.
“As such, drugs that IL-15 signaling pathways could be logically combined for additive anti-cancer immune activity in advanced tumors,” he said.
Reference: “Enhancing anti-tumor immunity of natural killer cells through targeting IL-15R signaling” by Iva Nikolic, Joseph Cursons, Benjamin Shields, Stephane Chappaz, Harrison Sudholz, Xiangpeng Meng, Patrick Constantinescu, Reshma Vijayakumaran, Michael D’Angelo, Momeneh Foroutan, David Ladd, Matthew Veldman, Jason Glab, Tahlia Procter, Hae-Young Park, Julian Contet, Felix Deuss, Kahlia Wong, Yi Sun, Richard Berry, Jai Rautela and Nicholas D. Huntington, 12 June 2025, Cancer Cell.
DOI: 10.1016/j.ccell.2025.05.011
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1 Comment
First off IL-15 is a cytokine and not genetic switch The data is from 2000 if you know the literature that affects NKs and CD8 CTL