Here, we illustrated that TREM2 inhibition could simultaneously solve the two intractable problems of radioresistance and immune escape in GBM through directly interfering with DNA damage repair pathway, regulating the high mobility group box 1 (HMGB1)/TREM2 positive feedback loop that cascaded the activation of Toll-like receptor 4 (TLR4)/protein kinase B(Akt) signaling pathway to decrease the secretion of pro-tumor and immunosuppressive cytokines, and inducing the polarization of immune cells towards anti-tumor phenotypes (Fig. 1). This evidence concerns the gene HMGB1 and glioblastoma.