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Sharma et al. Cancer Drug Resist 2023;6:688-708 https://dx.doi.org/10.20517/cdr.2023.82 Page 700

Figure 3. Potential new approaches to improve glioblastoma treatment. (A) The focused ultrasound in combination with micro-bubbles
and photodynamic therapy (PDT) can temporarily open BBB to allow therapeutics crossing. PDT can also activate local immunity in
TME; (B) New approaches to modulate glioblastoma TME by targeting hypoxia, activating suppressed local immunity, or enhancing
cancer neoantigen formation in tumor cells; (C) Novel nanodrug delivery technologies in combination with CRISPR/Cas9-based gene
editing and immune checkpoint inhibitors; (D) Various forms of adoptive cell therapies; (E) Better strategies for tumor stratification,
prognostic prediction and personalized medicine would enhance the clinical outcome of glioblastoma treatment. (Created with
BioRender.com). BBB: Blood-brain barrier; DC: dendritic cell; TAMs: tumor-associated macrophages; TME: tumor microenvironment.

The approval of 5-ALA by the FDA for fluorescence-guided glioblastoma resection has sparked a renewed
interest in its potential application for PDT .
[182]

Nanotechnology has also made significant advancements in the field of glioblastoma treatment. Various
forms of nanomedicines have exploited the features of the glioblastoma tumor microenvironment for
efficient BBB crossing and release of payloads [189-191] . Fan et al. engineered an MMP-2-activated nanoparticle
to carry anti-CD276 & CD3 bispecific antibodies and demonstrated that this strategy enhanced IFN-γ-
induced tumor cell ferroptosis . A polylactic-co-glycolic acid (PLGA) nanoparticle encapsulated
[192]
disulfiram was used to block hypoxia-induced NF-κB signaling and glioma stem cells . Zou et al. devised a
[193]
polymer-based CRISPR-Cas9 nano-capsule for systemic gene therapy delivery to glioblastoma . This
[194]
nano-capsule has both the BBB crossing and tumor targeting functions mediated through an angiopep-2
peptide . By targeting polo-like kinase (PLK-1) via a sgRNA, the strategy demonstrated a significant
[195]
survival advantage over the control mice .
[194]
CONCLUSION
Despite advances in surgical technologies and therapeutics development, there has been limited
improvement in the long-term survival rate of glioblastoma patients, with a 5-year survival still around 5%-
10%. Many lessons have been learned in glioblastoma drug resistance mechanisms, especially with cutting-
edge scRNAseq, spatial biology, and other-omics platforms. Efforts are needed to overcome BBB and tumor
heterogeneity, targeting glioma stem cells and their niches, enhancing T cell trafficking and preventing their