Glioblastoma is the most aggressive form of malignant brain cancer, characterized by an immunosuppressive microenvironment and extensive angiogenesis. Epidermal growth factor-like protein 7 (EGFL7), a secreted pro-angiogenic factor that is highly expressed in the glioblastoma microenvironment (GME), has been implicated in immune evasion by other solid tumors, but its role in glioblastoma immune regulation remains unclear. Here, we studied the impact of EGFL7 in shaping the immune landscape in glioblastoma and identified underlying mechanisms. Single-cell transcriptomic profiling of immune cells from glioblastoma models revealed that EGFL7 promotes an immunosuppressive GME, characterized by increased infiltration of pro-tumorigenic macrophages and enhanced T cell exhaustion. Mechanistically, EGFL7 interacts with integrin β2 (ITGB2) on immune cells to mediate these effects. Genetic perturbation of the EGFL7-ITGB2 axis attenuated immunosuppression and significantly prolonged the survival of glioblastoma-bearing mice. In conclusion, our study provides unequivocal evidence that the EGFL7-ITGB2 axis acts as a critical mediator of immunosuppression in glioblastoma and represents a potential therapeutic target for reprogramming the GME to prevent immune evasion in glioblastoma.