Fighting colorectal cancer metastases: a new ally for natural killer cells
Colorectal cancer (CRC) is the second biggest cause of cancer-related deaths worldwide. Although it has become much more treatable in recent years, the therapies used are still not effective for all patients. The high mortality rate associated with this type of cancer is primarily due to its ability to spread to other parts of the body, resulting in metastasis in a significant proportion of patients.
In this context, natural killer (NK) cells are a type of white blood cell belonging to the innate immune system, which can help combat the spread of cancer. Their name derives from their ability to spontaneously recognise and destroy cancer cells and inhibit the formation of metastases. Despite this, the behaviour of natural killer cells in relation to metastases that have already formed, particularly in the liver, remains unclear.
In research supported by the AIRC Foundation for Cancer Research, immunologist Giovanni Bernardini and his team studied the specific role of natural killer (NK) cells in the metastatic environment, with the aim of understanding how to better protect and preserve their anti-tumour capabilities. The research, coordinated by the Department of Molecular Medicine of Sapienza University was conducted in collaboration with several national and international groups. The results, published in the Journal of Clinical Investigation, revealed a natural defence mechanism that could help to slow the growth of liver metastases.
In particular, a research group led by Professor Benardini — an immunology specialist at Sapienza University — demonstrated that not all liver metastases are identical. Some types form microenvironments that boost the activity of natural killer (NK) cells, thanks to the presence of molecules that promote the survival of these cells and their ability to attack the tumour.
In the study, researchers analysed liver metastases obtained from mice and patients, finding that a specific type of macrophage — the so-called 'scavengers' of the immune system — can teach 'natural killer' cells to activate correctly and attack cancer cells.
“To do this, macrophages produce two chemokines,” says Giovanni Bernardini. These special proteins, called CXCL9 and CXCL10, act as chemical messengers, attracting NK cells into the metastases and creating an environment that allows these cells to activate.”
Some of the collected results highlight the significant importance of the chemokines CXCL9 and CXCL10. Notably, mice with a CXCR3 receptor deficiency, who can 'feel' the effects of these two proteins, exhibit inhibited natural killer cells and accelerated metastasis growth.
Overall, the published data show that effective collaboration between macrophages and natural killer cells is crucial for triggering an immune response that can restrict the progression of colorectal cancer. This opens up new therapeutic possibilities based on strengthening this network.
References
E. Russo, C. D’Aquino, C. Di Censo, M. Laffranchi, L. Tomaipitinca, V. Licursi, S. Garofalo, J. Promeuschel, G. Peruzzi, F. Sozio, A. Kaffke, C. Garlanda, U. Panzer, C. Limatola, C.A.J. Vosshenrich, S. Sozzani, G. Sciumè, A. Santoni, G. Bernardini. Cxcr3 promotes protection from colorectal cancer liver metastasis by driving NK cell infiltration and plasticity. Journal of Clinical Investigation. 2025;135(11):e184036. https://doi.org/10.1172/JCI184036
Further Information
Giovanni Bernardini
Department of Molecular Medicine