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inhibition, iNOS production was increased in glioma-associated microglia along with concomitant decrease
in IL-10 gene expression [94,95] . Moreover, several preclinical studies have demonstrated that siRNA inhibition
of STAT3 in glioma cells leads to microglial activation and tumor growth inhibition in murine models, with
increases in IL-2, IL-4, IL-12, IL-15, and CXCL10, along with upregulation of CD80 and CD86 on myeloid
cells [94,96] .

Finally, the production of HIF-1α, vascular endothelial growth factor (VEGF), and CXCL2 in myeloid and
[97]
glioma cells have long since been known to have roles in tumor angiogenesis [Figure 2E] . Specific to
microglia however is CXCL12 and its ligand CXCR4, which have been implicated in radiation resistance
[98]
and increased tumor vasculogenesis. Tabouret et al. demonstrate that with tumor recurrence, there is a
switch in expression profile from VEGFR3-HIF-1α to CXCL12-CXCR4 predominance in glioma-associated
microglia. As such, microglia may have roles in propagating additional mechanisms of immune resistance in
tumor recurrence, providing another rationale for studying and targeting this population to optimize anti-
tumor strategies [Figure 2E].

CONCLUSION
In this review, we discussed the importance of the roles that microglia and macrophages play in GBM.
These two cell types have been shown to be complicit in contributing to an immunosuppressed and/or
tumor-progressive milieu; however, more data need to be collected on the interactions between microglia
and macrophages within these populations in the TME. This review also highlights the importance of
semantically distinguishing between microglia and macrophages. As there are certain cancer-specific
interactions with either microglia or macrophages, we recommend clearly delineating between the two in
order to avoid complicating future experimental designs and discussions. Furthermore, this review provides
a note of caution in strictly following the M1/M2 phenotype for macrophages and microglia, as they are
complex and have several differences with each other that make this transposed classification scheme
largely unfounded. However, it is this same complexity we appreciate for the potential exploration of new
pathways; we look forward to further studying these populations and pathways to work towards a clearer
understanding of immunotherapy for GBM.

DECLARATIONS
Authors’ contributions
Conceived of the presented idea: Choi J, Lim M
Underwent literature review and synthesized a draft: Choi J
Looked over and edited draft: Lim M, Mai N, Jackson C, Belcaid Z
Developed the figures and tables and organized the final draft: Choi J, Mai N
Contributed ideas throughout the process and approved the final draft: Lim M

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.