Glioblastoma glycolytic signature predicts unfavorable prognosis, immunological heterogeneity, and ENO1 promotes microglia M2 polarization and cancer cell malignancy

Abstract Glioblastomas are the most malignant brain tumors, whose progress was promoted by aberrate aerobic glycolysis. The immune environment was highly engaged in glioblastoma formation, while its interaction with aerobic glycolysis remained unclear. Herein, we build a 7-gene Glycolytic Score (GS) by Elastic Net in the training set and two independent validating sets. The GS predicted malignant features and poor survival with good performances. Immune functional analyses and Cibersort calculation identified depressed T cells, B cells, natural killer cells immunity, and high immunosuppressive cell infiltration in the high-GS group. Also, high expressions of the immune-escape genes were discovered. Subsequently, the single-cell analyses validated the glycolysis-related immunosuppression. The functional results manifested the high-GS neoplastic cells’ association with T cells, NK cells, and macrophage function regulation. The intercellular cross-talk showed strong associations between high-GS neoplastic cells and M2 macrophages/microglia in several immunological pathways. We finally confirmed that ENO1 , the key gene of the GS, promoted M2 microglia polarization and glioblastoma cell malignant behaviors via immunofluorescence, clone formation, CCK8, and transwell rescue experiments. These results indicated the interactions between cancerous glycolysis and immunosuppression and glycolysis’ role in promoting glioblastoma progression. Conclusively, we built a robust model and discovered strong interaction between GS and immune, shedding light on prognosis management improvement and therapeutic strategies development for glioblastoma patients.