Colorectal cancer is the third most common tumor worldwide, and in more than half of cases it is accompanied by the spread of metastases to the liver, resulting in a marked worsening of prognosis. Understanding the behavior of these metastases – particularly how malignant colorectal cells adapt to the liver environment by developing strategies different from those of the primary tumor – is essential to opening new therapeutic avenues.

In this context as well, the relationship between the immune system and cancer represents one of the most stimulating frontiers of modern oncology. Two complementary studies, recently published in The Journal of Clinical Investigation and Cancer Immunology Research, analysed primary colorectal tumors, liver metastases, and blood samples taken from the same patients. The goal was to investigate how the innate immune system – particularly two types of cells, tumor-associated macrophages and Natural Killer (NK) cells – behaves in the three different tissues, and how these differences might translate into new treatment opportunities.

The studies were conducted by the research group led by Domenico Mavilio – Head of the Clinical and Experimental Immunology Lab at Humanitas Research Hospital, in collaboration with Guido Torzilli, director of the General Surgery and Hepatobiliary Surgery Division at Humanitas Research Hospital and full professor at Humanitas University. The Humanitas research groups led by Cecilia Garlanda, Alberto Mantovani, Ana Lleo, and Massimo Locati, as well as the Pathology Unit, contributed to the two studies.

The role of macrophages in tumor progression

Macrophages are immune cells tasked with defending the body, but within the tumor environment they may take on ambivalent functions. Due to these characteristics, they are called TAMs (Tumor-Associated Macrophages). The study published in Cancer Immunology Research shows – using samples from patients who underwent simultaneous surgery for colorectal cancer and liver metastases – how TAMs from the primary tumor possess features that differ significantly from those of TAMs found in metastases.

Specifically, TAMs in primary colorectal lesions display a predominantly pro-inflammatory profile, yet at the same time promote immune evasion by the tumor and thus disease progression. Conversely, in the liver, metastases are dominated by immunoregulatory, highly proliferative TAMs, which contribute to creating a strongly immunosuppressive environment. This, in turn, facilitates tumor growth and is associated with poor prognosis. In this way, colorectal cancer cells show a remarkable ability to adapt to the tissue in which they are, modulating local immune responses to promote their own survival.

NK cells and new therapeutic strategies

The study published in The Journal of Clinical Investigation examines another type of immune cell – Natural Killer (NK) cells – and their role within the microenvironment of liver metastases. In this setting, researchers observed the presence of a predominant NK subpopulation characterized by high levels of the surface protein CD56 and strong production of interferon gamma (IFNγ), a key molecule in anti-tumor response. However, the ability of NK cells to effectively control metastatic growth in the liver is reduced due to their concurrent production of immune checkpoint molecules, which act to “turn off” immune defense activity.

The studies identified two promising therapeutic targets to reactivate these cells: IL-1R8 (SIGIRR) and CXCR4. Using specific monoclonal antibodies to block these immune checkpoints in NK cells can restore the production of antitumor molecules such as TNFα and IFNγ.

From research to clinical perspective

The results of these studies represent a concrete example of translational research, where analysis of immune mechanisms underlying metastatic progression can guide the development of new treatments. Understanding how innate immunity is reshaped in the transition from the primary tumor to metastatic tissue not only clarifies fundamental aspects of colorectal cancer biology but also lays the groundwork for more targeted and rational therapeutic approaches.

“Combining the reactivation of hepatic NK cells with a strategy to reprogram TAMs from an immunosuppressive to an antitumor profile,” concludes Domenico Mavilio, “could represent a combined action that could open the door to enhancing existing immunotherapies and improving prognosis in patients with colorectal cancer metastatic to the liver.”