Targeting the CCL2-CCR2 axis in cancer: insights into in vitro screening and humanized mice.

Abstract

An immunosuppressive tumor microenvironment that facilitates cancer progression is an important challenge in combating the disease. The CCL2-CCR2 axis is a primary facilitator in this process, facilitating the recruitment of CCR2-positive myeloid cells, including M-MDSCs and TAMs, to tumor and metastatic locations. CCR2 is also expressed on tumor cells and regulatory T cells, further enhancing cancer cell motility and immune suppression. Inhibition of this system through genetic deletion or small-molecule inhibitors significantly reduces primary tumor and metastasis in preclinical models, highlighting CCR2 as a promising therapeutic target. Although several CCR2 inhibitors have entered clinical trials, differences in their potency and the limited predictability of murine models have hampered clinical translation. The current work by Sugiyama et al. carefully evaluated 10 human CCR2 antagonists, identifying MK0812 as the most effective inhibitor. Using human CCR2B knock-in mice, they established a practical platform for evaluating CCR2-targeted drugs with direct relevance to human cancer therapy, highlighting the importance of humanized models for translational immuno-oncology.