Macrophages and microglia in glioblastoma: heterogeneity, plasticity, and therapy

Abstract

Glioblastoma (GBM) is the most aggressive tumor in the central nervous system and contains a highly immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages and microglia (TAMs) are a dominant population of immune cells in the GBM TME that contribute to most GBM hallmarks, including immunosuppression. The understanding of TAMs in GBM has been limited by the lack of powerful tools to characterize them. However, recent progress on single-cell technologies offers an opportunity to precisely characterize TAMs at the single-cell level and identify new TAM subpopulations with specific tumor-modulatory functions in GBM. In this Review, we discuss TAM heterogeneity and plasticity in the TME and summarize current TAM-targeted therapeutic potential in GBM. We anticipate that the use of single-cell technologies followed by functional studies will accelerate the development of novel and effective TAM-targeted therapeutics for GBM patients.

Figure 1. TAM origin, identity, and heterogeneity in GBM.

TAMs in GBM include brain-resident microglia and macrophages that arise from the yolk sac and bone marrow and can be characterized as CD11b⁺CD45^lo and CD11b⁺CD45^hi cells, respectively. In addition to specific markers, microglia can be distinguished from macrophages using advanced approaches (e.g., single-cell technologies, genetically engineered mouse models, lineage tracing, and intravital two-photon microscopy). TAM heterogeneity is regulated in a context-dependent manner (e.g., distinct tumor origins, genetic and epigenetic alterations, treatments, and sex of the host). TAMs are typically characterized as immunostimulatory (antitumor) and immunosuppressive (protumor) phenotypes. However, single-cell technology development expands our understanding of this plasticity in GBM.

Figure 2. Identification of new TAM subpopulations in GBM.

The understanding of TAM heterogeneity and functional plasticity in the GBM TME is expanding with the development of single-cell technologies (e.g., scRNA-Seq and CyTOF). Unbiased pathway analyses followed by functional validations would help characterize context-dependent TAM functions. Notably, quite a few TAM subpopulations and their potential biological functions have been identified and deciphered (as indicated). CD73, cluster of differentiation 73; CyTOF, cytometry by time of flight; GBM, glioblastoma; HGG-AM, high-grade glioma–associated microglia; HMOX1, heme oxygenase 1; MARCO, macrophage receptor with collagenous structure; scRNA-Seq, single-cell RNA sequencing; TAM, tumor-associated macrophage; TME, tumor microenvironment.

Figure 3. Current TAM-targeted therapeutic approaches in GBM.

Depending on the working mechanisms, strategies for targeting TAMs include (a) targeting TAM recruitment; (b) targeting TAM immunosuppressive reprogramming; (c) targeting new TAM subpopulations; and (d) targeting TAM-mediated phagocytosis. The key targets and associated drug candidates are indicated. 4-1BB, TNF receptor superfamily member 9; AHR, aryl hydrocarbon receptor; BACE1, β-site amyloid precursor protein–cleaving enzyme 1; BAPN, β-aminopropionitrile; CCR2, C-C motif chemokine receptor 2; CHI3L1, chitinase-3–like 1; CLOCK, circadian locomotor output cycles protein kaput; CSF-1, colony-stimulating factor 1; CSF-1R, CSF-1 receptor; GAL3, galectin-3; Gal3BP, galectin-3–binding protein; HMOX1, heme oxygenase 1; Kyn, kynurenine; LGMN, legumain; LOX, lysyl oxidase; MAGL, monoacylglycerol lipase; MARCO, macrophage receptor with collagenous structure; OLFML3, olfactomedin-like 3; OPN, osteopontin; PGE₂, prostaglandin E₂; PSGL-1, P-selectin glycoprotein ligand-1; ROBO1/2, roundabout receptor 1/2; SELP, P-selectin; SIRPα, signal-regulatory protein-α; SLIT2, slit guidance ligand 2; TβRI, TGF-β receptor type I.