Interactions and communications in the glioblastoma microenvironment: potential targets for chemo-/radiotherapy.

Glioblastoma therapy remains constrained by a highly interactive tumor microenvironment (TME) that stimulates invasion, resistance, and immune suppression. The glioblastoma TME comprises malignant astrocytic and stem-like tumor cells, resident microglia, infiltrating immune cells, endothelial cells, and a modified extracellular matrix (ECM) that together establish an immunosuppressive tumor stroma. Communication among these elements proceeds through cytokines, chemokines, growth factors, extracellular vesicles, metabolic exchange, and direct cell-matrix contacts. These interactions modulate DNA damage responses (DDRs); remodel immune responses by immunosuppressive and antitumor immune cells; alter the activity of stromal cells; and change angiogenesis, metastasis, and cell survival pathways-which in turn induce resistance to chemo-/radiotherapy. Chemotherapy and radiotherapy induce acute and chronic changes in the TME, including the recruitment of immunosuppressive cells, upregulation of survival signaling in perivascular niches, vascular remodeling, and hypoxia/metabolism rewiring that diminishes the efficacy of chemo-/radiotherapy. Preclinical and early clinical interventions show that targeting cells and their secretions in the TME can be suggested for reprogramming the glioblastoma TME and the subsequent resistance to chemo-/radiotherapy. The focus of this review is to provide mechanistic evidence linking TME communication networks to chemo-/radiotherapy resistance. Strategies that target these interactions to identify translational pathways for combination therapies are reviewed.