Summary

Colorectal cancer (CRC) is a heterogeneous disease at molecular level leading to heterogeneous outcomes, therapy, drug responses and primary or secondary resistance to targeted treatments. This heterogeneity represents a major challenge for precise interpretation of prognostic and predictive markers. Whereas primary colorectal cancer without metastasis is mostly curable by surgical resection and adjuvant systemic therapy, metastatic disease remains largely incurable and is still a major life-threatening situation. Preclinical studies so far rarely focus on the metastatic situation but focus on the primary tumor. Therefore, it is critical to expand these preclinical studies to the process of metastasis and to develop metastasis-specific therapeutic approaches. It is well known since Virchow that there is an association between cancer and the immune system and now it is well described that the tumor microenvironment plays a critical role in carcinogenesis. Dissemination and metastasis is only facilitated when tumors evade detection and destruction by the immune system and it is assumed that immune subversion by primary tumors plays an essential role in enabling metastatic spread to distant organs and spread of tumor-induced inflammation to become systemic plays a critical role in metastasis. Thus, there is an urgent need to deepen our fundamental understanding of immune cell crosstalk in cancer especially for metastatic cancer, how this crosstalk can be manipulated for direct therapeutic targeting or can be modulated that conservative therapeutic approaches are more efficient. Suggesting that treatment approaches for CRC metastasis should include considerations about the underlying tumor microenvironment in the specific metastasis location and possible adapted immunomodulation strategies. It is well described that the microbiome impacts colorectal carcinogenesis. As metastasis of colorectal cancer are not a sterile microenvironment either. We hypothesized that bacteria also regulate the process of metastasis. Therefore to understand the cellular and microbial landscape of the metastatic tumor microenvironment and the intercellular interactions in the metastasis of CRC is a critical prerequisite for the design of new immunotherapeutic treatment strategies.