Insights into the co-evolution of glioblastoma and associated macrophages

Glioblastoma (GBM) is one of the most immunosuppressive and heterogeneous tumors with limited treatment options. Most studies relied on treatment-experienced patient samples to elucidate the origins of tumor heterogeneity, introducing bias into the analysis. The analysis of samples from multifocal GBM patients, in which independent lesions arise from the same progenitor and undergo parallel evolution, enables the study of the natural evolution of GBM while removing the effect of therapy on the emergence of heterogeneity. This enables the identification of critical events in the evolution of GBM and the unbiased study of subtype progression, diversity, and invasive potential. The tumor microenvironment of GBM undergoes significant changes throughout tumor progression. Recent studies have highlighted the switch from an abundance of resident microglia-derived macrophages in earlier stages to the prevalence of blood-derived macrophages in later stages of GBM. There is conclusive evidence that these alterations cannot be viewed in isolation and that the tumor microenvironment co-evolves with tumor cells during cancer progression. Together with an increasingly hypoxic environment, this culminates in highly immunosuppressive conditions, resulting in a feedback loop further reinforcing evolutionary changes in the tumor. A new study now provides a unique look at the natural evolution of GBM, identifies critical events in its development, and has the potential to help improve the diagnosis and therapy of this deadly disease.