The cellular interactions in the tumor microenvironment of colorectal cancer (CRC) are poorly understood, hindering patient treatment. In the current study, we investigate whether events occurring at the invasion front are of particular importance for CRC treatment strategies. To this end, we analyze CRC tissues by combining spatial transcriptomics from patients with a public single-cell transcriptomic atlas to determine cell-cell interactions at the invasion front. We show that CRC cells are localized specifically at the invasion front. These cells induce human leukocyte antigen G (HLA-G) to produce secreted phosphoprotein 1 (SPP1)+ macrophages while conferring CRC cells with anti-tumor immunity, as well as proliferative and invasive properties. Taken together, these findings highlight the signaling between CRC cell populations and stromal cell populations at the cellular level. Display omitted •Spatial and single-cell atlas of human normal and cancer colorectal tissues•Colorectal cancer cells at the invasive front co-localize with macrophages•Spatial intercellular communication occurs between tumor cells and stromal cells•HLA-G is essential for anti-tumor immunity in colorectal cancer Ozato et al. utilize a spatial transcriptome analysis approach to identify malignant crosstalk among co-localized cells in the cancer microenvironment. CRC cells localized at the invasion front induce HLA-G to produce SPP1+ macrophages, simultaneously conferring anti-tumor immunity as well as proliferative and invasive properties to CRC cells.