Colorectal Liver Metastasis: Can Cytokines Make the Difference?

SIMPLE SUMMARY: Colorectal cancer (CRC) is one of the most common malignancies worldwide, with a mortality rate of 86%. The main cause of death is the development of colorectal liver metastases (CRLMs). The communication between cancer cells and the environment is a prerequisite for generating a favorable tumor microenvironment, and it is mediated by soluble molecules such as cytokines, growth factors, and extracellular vesicles. Mounting evidence suggests that cytokines play a decisive role in CRC progression and metastasis. In this review, we highlight the involvement of different cytokines during the development of CRLMs and emphasize the complexity as well as therapeutic implications of the cytokine milieu. ABSTRACT: Colorectal cancer (CRC) is the third leading cause of cancer-related death worldwide. Metastasis is the prime driver of CRC-related mortality, and the liver is the organ most frequently involved. Despite the overall success of current treatments, colorectal liver metastasis (CRLM) is associated with poor prognoses and a survival rate of only 14%. Recent studies have highlighted the importance of the tumor microenvironment (TME) and the crosstalk within it in determining the invasion of distant organs by circulating cancer cells. In the TME, cellular communication is mediated via soluble molecules, among which cytokines have recently emerged as key regulators, involved in every aspect of tumor progression and the metastatic cascade. Indeed, in the serum of CRC patients elevated levels of several cytokines are associated with cancer development and progression. The current review evaluates the role of different cytokines during CRLM development. Additionally, considering the increasing amount of data concerning the importance of cytokine complex networks, we outline the potential of combination treatments using targeted cytokines together with other well-established therapies, such as immune checkpoint blockades, chemotherapy, or gene therapy, to improve therapeutic outcomes.