Tumor-associated macrophages (TAMs) account for 30-50% of glioma microenvironment. The interaction between glioma tumor cells and TAMs can promote tumor progression, but the intrinsic mechanisms remain unclear. Herein, we reported that soluble LRIG3 (sLRIG3) derived from glioma tumor cells can block the M2 polarization of TAMs via interacting with NETO2, thus suppressing GBM malignant progression. The expression or activity of ADAM17 in glioma cells was positively correlated with the expression of sLRIG3 in cell supernatant. Soluble LRIG3 can suppress the M2-like polarity transformation of TAMs and inhibit the growth of tumor. High expression of LRIG3 predicts a good prognosis in patients with glioma. Mass spectrometry and Co-immunoprecipitation showed that sLRIG3 interacts with the CUB1 domain of NETO2 in TAMs. Silencing or knockout of NETO2 could block the effect of sLRIG3, which inhibited the M2-like polarity transformation of TAMs and promoted GBM tumor growth. However, overexpressing His-target NETO2 with CUB1 deletion mutation does not fully recover the suppressive effects of sLRIG3 on the TAM M2-polarization in NETO2-Knockout TAMs. Our study revealed vital molecular crosstalk between GBM tumor cells and TAMs. Glioma cells mediated the M2 polarization of TAM through the sLRIG3-NETO2 pathway and inhibited the progression of GBM, suggesting that sLRIG3-NETO2 may be a potential target for GBM treatment.© 2023. The Author(s).