EGFRvIII-Positive Glioblastoma: Structural Rewiring, Immune Microenvironmental Remodeling, and Therapeutic Resistance

Glioblastoma (GBM) harboring EGFRvIII represents a biologically distinct and highly aggressive tumor subset characterized by aberrant receptor signaling, marked intratumoral heterogeneity, and profound immune remodeling. Rather than acting as a constitutively active truncated receptor, EGFRvIII represents a structurally rewired EGFR variant whose altered extracellular architecture, receptor assembly, and trafficking promote ligand-independent signaling and signaling plasticity, thereby supporting tumor proliferation, stemness, invasion, and angiogenesis. Beyond tumor-intrinsic effects, EGFRvIII also contributes to the formation of a spatially heterogeneous, myeloid-dominant and immunosuppressive tumor microenvironment, characterized by myeloid-cell expansion, impaired T cell effector function, and mesenchymal-like tumor-immune plasticity. Despite extensive therapeutic efforts including tyrosine kinase inhibitors, monoclonal antibodies, vaccines, immune checkpoint blockade, and EGFRvIII-targeted CAR-T cell strategies, durable clinical efficacy remains limited by the interplay of antigen heterogeneity, adaptive signaling, clonal evolution, and microenvironmental immunosuppression. Taken together, EGFRvIII can be viewed as a structural and evolutionary regulator that links receptor rewiring and signaling plasticity with immune ecosystem remodeling and therapeutic resistance, underscoring the need for integrated strategies that target both tumor cell-intrinsic signaling and the suppressive microenvironment.