Tumor-associated macrophage-related strategies for glioma immunotherapy

Abstract

High-grade glioma is one of the deadliest primary tumors of the central nervous system. Despite the many novel immunotherapies currently in development, it has been difficult to achieve breakthrough results in clinical studies. The reason may be due to the suppressive tumor microenvironment of gliomas that limits the function of specific immune cells (e.g., T cells) which are currently the primary targets of immunotherapy. However, tumor-associated macrophage, which are enriched in tumors, plays an important role in the development of GBM and is becoming a research hotspot for immunotherapy. This review focuses on current research advances in the use of macrophages as therapeutic targets or therapeutic tools for gliomas, and provides some potential research directions.

Fig. 1. Three major classes of TAM-targeted glioma therapies.

TAM mainly originates from microglia in the brain and peripheral-derived monocytes, and its activation types contribute to a suppressive immune microenvironment and thus results in various tumor biological behavior. As a result, TAM-targeted therapy mainly targets its recruitment, polarization, and its multiple function in tumor behavior. TAM tumor-associated macrophage, CCL chemokine ligand, CYP cytochrome P450, CSF colony-stimulating factor, VEGF vascular endothelial growth factor, HIF-1 hypoxia-inducible factors-1 (Created with BioRender.com).

Fig. 2. Exploiting engineered macrophages for glioma therapy.

Because of its tumor tropism, macrophages are ideal vehicle to carry therapeutic matters to tumor site. General payloads include conventional chemotherapy drugs, medium of the physical treatments, and genes of immunotherapeutic biomolecules. Latest technology also enables loading of CARs on macrophages, potentially breaking through the limitations of CAR therapy in solid tumors. pCAR chimeric antigen receptor plasmid, PDT photodynamic therapy, CPN conjugated polymer nanoparticles, TMZ NP temozolomide nanoparticle, DOX doxorubicin, PTX paclitaxel, CD cytosine deaminase, IFN interferon, NS nanoshells, EGFRv epidermal growth factor variant, BiTE bispecific T-cell engagers (Created with BioRender.com).