An Overview the Role of the CCL2/CCR2/IL-6 Axis in Glioma Progression: Mechanisms, Microglial Reprogramming, and Therapeutic Implications

Abstract

Gliomas are the most frequently occurring brain cancers defined by aggressive, invasive, and chemoresistant growth patterns. These tumors are responsible for a complex immunosuppressive tumor microenvironment mainly dictated by tumor-associated macrophages, including brain-resident microglia and bone-marrow-derived macrophages. Gliomas utilize the CCL2/CCR2/IL-6 axis to recruit and reprogram microglia to a tumor-supportive phenotype. This review article investigates the role of the CCL2/CCR2/IL-6 axis in glioma pathophysiology through elaborate in vitro, in vivo, and transcriptomic methodologies. Therapy targeting this pathway has yielded promising results so far. For instance, preclinical studies revealed that pharmacological inhibition of either CCR2 or IL-6R reduces tumor-associated macrophages (TAMs) recruitment and impairs glioma growth. Nevertheless, several hurdles remain, including species differences that limit the translation of findings to humans due to inherent differences in immune system regulation and tumor biology between commonly used animal models, such as rodents, and humans. Furthermore, incomplete differentiation between microglia and bone marrow-derived macrophages (BMDMs), and systemic effects due to inhibition of these pathways pose significant challenges. Further studies using human-derived models, spatial transcriptomics, and personalized therapies hold future promise for better treatment modalities for glioma.