macrophages have been identified as key players in the colorectal cancer (CRC) tumor microenvironment, but their function remains unclear. This study integrated single-cell and spatial transcriptomics with bulk sequencing to investigate the roles and mechanisms of macrophages in CRC. Our findings revealed a pronounced elevation of macrophages in CRC, especially within tumor territories. These macrophages served as markers for CRC initiation, progression, metastasis, and potential prognosis. Furthermore, they showed heightened transcriptional activity in genes linked to angiogenesis, epithelial-mesenchymal transition, glycolysis, hypoxia, and immunosuppression. protein amplified CRC cell migration and invasion, potentially mediating cellular crosstalk via the , , and complex axes. Patients with a high proportion of macrophages could benefit more from immune checkpoint blockade therapy. Interestingly, expression was significantly enriched in  macrophages versus macrophages, possibly explaining limited anti-CSF1R monotherapy effects. In conclusion, we propose an macrophage model in CRC, highlighting such macrophages as a promising therapeutic target due to their malignancy markers.