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exhaustion, and modulating the immunosuppressive TME in glioblastoma. A complex disease, such as
glioblastoma, would require a complex solution. Multidisciplinary approaches involving nanodrug carriers,
focused ultrasound, plus temporary BBB permeability enhancement technologies (micro-bubbles,
phototherapy) in combination with gene and immuno-therapy will likely lead to an improved outcome
[Figure 3]. In addition, a much less traveled path is to enhance glioblastoma neoantigen formation.
Glioblastoma tumors have a relatively lower TMB, which was shown to correlate with immunotherapy
outcomes in solid tumors [76,196] . Lower TMB results in lower neoantigen generation, which enables a stealth
mode of glioblastoma cells. Therefore, increasing the formation of neoantigens may significantly promote
tumor recognition and clearance by the immune system . Besides T cells, strategies to activate other
[197]
infiltrating immune cells (TAMs, microglia, and MDSCs) that reside in the glioma TME in large abundance
may effectively reverse the local immunosuppression. Finally, a more precise tumor stratification approach
and improved prognostic biomarkers will help determine the most effective combinatorial therapies for
glioblastoma treatment.

DECLARATIONS
Authors’ contributions
Conceptualization, investigation, writing: Sharma S, Chepurna O
Conceptualization, supervision, writing: Sun T

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.

Consent for publication
Not applicable.

Copyright
© The Author(s) 2023.

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