Background Glioma is the most aggressive form of primary brain tumor, characterized by immune evasion, rapid growth, extensive angiogenesis and peritumoral invasion into the brain parenchyma. Recent evidence indicates that epidermal growth factor-like protein 7 (EGFL7), a known angiogenic factor, is highly expressed in the glioma microenvironment (GME). As EGFL7 has been implicated in immune evasion of lung and breast cancer, we undertook in vivo studies using mouse models to uncover whether EGFL7 regulates immune evasion in glioma and to determine the underlying mechanism. Our study provides unequivocal evidence to show that EGFL7 alters glioma-resident immune cells and induces immunosuppression in the GME. Materials and Methods By implanting murine glioma cells into immunocompetent mice, we studied the role of EGFL7 in influencing the immune system in glioma. After 4 weeks of tumor growth, immune cells from the extracted tumor tissue were isolated and analyzed by employing single cell RNA sequencing (scRNA-seq) and flow cytometry. In addition, co-immunoprecipitation and mass spectrometry were utilized to uncover the different interacting partners of EGFL7 protein in the GME. Results Our findings demonstrate that EGFL7 expression is detrimental for survival of glioma bearing mice while its elimination prolongs survival. Using scRNA-seq and flow cytometry, we identified that EGFL7 induces an immunosuppressive environment in a gain-of-function study. An increased infiltration of specific pro-tumorigenic immune cells such as anti-inflammatory macrophages and myeloid-derived suppressor cells was observed in the presence of ectopic EGFL7 compared to control tumor tissues. In particular, EGFL7 protein had a major impact on the lymphoid population, especially the T cells. Concurrently, knocking out EGFL7 in a loss-of-function study led to rescue of the immunosuppression effect observed in the gain-of-function study.Using co-immunoprecipitation, we uncovered an interaction between EGFL7 and integrin β2 (present on immune cells). In vivo studies and in vitro migration assays uncover that the interaction between EGFL7 and integrin β2 plays an important role in the infiltration patterns of different immune cell populations in the GME. Conclusions We believe that this interaction between EGFL7 and integrin β2 is potentially responsible for inducing an immunosuppressive environment and places EGFL7 and integrin β2 at the center of glioma immunotherapy.S. Mahajan: None. U. Schumann: None. M.H.H. Schmidt: None.