Altogether, the ligand–receptor-based interaction found in this study and from the literature strongly demonstrates the cross-talk between the high-GS glioblastoma cells and M2 macrophage/microglia, and the glioblastoma-derived ENO1’s roles in regulating microglia M2 polarization was subsequently verified by rescue experiment here, making their exposed interaction a promising target for further therapeutic strategy development. This evidence concerns the gene ENO1 and glioblastoma.