Metastatic cancer is aggressive and rapidly developing, making it difficult to treat, often leading to mortality. Cancer cells are not isolated, but rather survive and proliferate in complex tumor microenvironments. Importantly, tumor cells “educate” immune cells to play a supportive role during cancer progression. Therefore, understanding how cancer cells and immune cells communicate is of pivotal importance to limit tumor progression. In this project, we identified the chemokine receptor CXCR4 and its correspondent ligand, CXCL12, as a key couple that regulate the interaction between tumor cells and immune cells. The research has been performed using the zebrafish xenograft model. This model offers the advantage of looking at tumor-immune cell interaction on a single cell level and in a living whole organism. The transparency of the embryo and the current genetic tools available, in combination with the ease in pharmacological approaches, make this model an excellent tool to determine and impair cancer-microenvironment inter-communication. We showed that inhibiting the CXCL12-CXCR4 axis either on the tumor side or on the immune cell side leads to impaired tumor progression, during the early phases of metastasis formation. We propose that blocking cancer-stroma communication represents a promising therapeutic strategy to fight cancer.