Paved with good intentions: decoding macrophage heterogeneity in glioblastoma for targeted therapies

Abstract

The fight against cancer is complex, because tumors are not made up of cancer cells alone, but also include cells from our own immune system. Among these, macrophages are particularly abundant in many types of cancer. These immune cells typically maintain tissue repair and balance, but in tumors like glioblastoma, the most aggressive form of brain cancer, they are co-opted to promote tumor growth and suppress the immune response. Previous therapies that targeted all macrophages have proven largely ineffective, as macrophages are highly diverse: some macrophage subsets support the tumor, while others work against it. This dissertation focuses on understanding these differences, especially how tumors exploit normal macrophage functions, such as lipid metabolism. It was discovered that a specific subtype of lipid-rich macrophages in glioblastoma supports tumor growth by transferring lipids, such as cholesterol, to the tumor. Additionally, a follow-up study explores how nanotechnology can be used to deliver drugs specifically to these harmful macrophages. For example, drugs can be 'hidden' in remnants of myelin, a lipid-rich brain structure, which are preferentially taken up by these macrophages. This research provides new insights into how glioblastoma manipulates the immune system and lays the groundwork for developing targeted therapies against tumor-promoting macrophages, with the aim of more effectively combating this deadly tumor.