The intersection of chemokine signaling with the hallmarks of cancer in glioblastoma

Abstract

Glioblastoma, IDH-wildtype, is characterized by diffuse invasion, profound immunosuppression, treatment resistance, and near-inevitable recurrence. Although canonical genetic alterations establish malignant capacity, they do not fully explain how glioblastoma cells adapt to hypoxic, perivascular, invasive, immunosuppressive, metabolically constrained, and treatment-injured microenvironments. We examined how chemokine signaling contributes to these adaptive behaviors. We used the hallmarks of cancer as an organizing framework to synthesize preclinical, translational, and clinical evidence on chemokine circuits in glioblastoma. We evaluated recurrent mechanistic pathways, distinguished causal functions from context-dependent biomarker associations, and assessed their therapeutic relevance. Chemokines act primarily as spatial and stress-responsive regulators rather than initiating oncogenic drivers. Recurrent circuits include CXCL12–CXCR4 in vascular repair, invasion, and stem-like persistence; CCL2 and CCL7 signaling through CCR2 in suppressive myeloid recruitment and metabolic–immune remodeling; CCL5–CCR5 in perivascular protection, invasion, and DNA-damage tolerance; and CXCL8 signaling through CXCR1 and CXCR2 in angiogenesis, immune evasion, and therapy-induced plasticity. Most chemokine-directed strategies remain preclinical or early translational. Therapeutic development should prioritize biomarker-defined dependencies and appropriately timed combinations that disrupt selected chemokine-dependent interactions within specific biological and treatment contexts. Clinical translation will require verification of target engagement, disruption of the relevant cellular interactions, and evidence that chemokine modulation improves treatment response or delays recurrence.