Glioblastoma (GBM) remains one of the most lethal brain malignancies, with an abysmal five-year survival rate near 6 %. Despite advances in tumor biology, clinical outcomes have not improved, partially due to glioma stem cells (GSCs) that drive treatment resistance. Radial glial cells (RGCs), recognized as key progenitors in neurodevelopment, have recently gained attention in GBM research due to RGC-like populations being identified in GBM. RGCs have striking similarities with GSCs, including their mechanisms of self-renewal, pluripotency, and migration. This review highlights those parallels between as well as recent studies on their critical intersections to expand our comprehension of neurodevelopmental paradigms in GBM. Understanding these parallels may uncover developmental pathways that can be exploited to improve therapeutic strategies for GBM.

Background/Objectives: Glioblastoma (GBM) remains a lethal primary CNS malignancy with limited response to immunotherapy. Adoptive cellular therapy (ACT) improves survival in preclinical models, yet tumors ultimately recur. While T cell exhaustion is a common mechanism of resistance, the contribution of dendritic cell (DC) dysfunction remains unclear. We aimed to define mechanisms of immune escape following ACT, focusing on DC function and the role of hypoxia. Methods: Using a murine glioma model (KR158B), mice were treated with ACT consisting of tumor RNA–pulsed DC vaccines and adoptively transferred T cells. Tumor-infiltrating immune populations were analyzed by flow cytometry. DC function was assessed using T cell activation assays. Bulk RNA sequencing and gene set enrichment analysis were performed on sorted DCs. Hypoxia was modeled in vitro, and HIF1α was perturbed using CRISPR-mediated knockout. Results: ACT significantly increased survival but did not prevent tumor recurrence. Escaped tumors contained abundant cytotoxic, non-exhausted T cells, indicating that T cell dysfunction was not the primary driver of resistance. Instead, tumor-associated DCs exhibited impaired T cell activation despite preserved antigen uptake. Transcriptomic analyses revealed reduced antigen presentation and co-stimulatory signaling, alongside increased expression of tolerogenic factors. ACT-treated tumors demonstrated heightened hypoxia pathway activation, with elevated HIF1α expression in DCs. Hypoxia induced DC tolerogenic programs and reduced their ability to activate T cells, an effect partially reversed by HIF1α disruption. Increased immune infiltration and inflammation following ACT further amplified hypoxia signaling. Conclusions: DC dysfunction is a key mechanism of immune escape following ACT in glioma. Hypoxia-driven tolerization of DCs impairs sustained anti-tumor immunity, highlighting the hypoxia–DC axis as a promising therapeutic target to enhance immunotherapy efficacy.

Background/Objectives: Glioblastoma (GBM) remains a lethal primary CNS malignancy with limited response to immunotherapy. Adoptive cellular therapy (ACT) improves survival in preclinical models, yet tumors ultimately recur. While T cell exhaustion is a common mechanism of resistance, the contribution of dendritic cell (DC) dysfunction remains unclear. We aimed to define mechanisms of immune escape following ACT, focusing on DC function and the role of hypoxia. Methods: Using a murine glioma model (KR158B-luc), mice were treated with ACT consisting of tumor RNA-pulsed DC vaccines and adoptively transferred T cells. Tumor-infiltrating immune populations were analyzed by flow cytometry. DC function was assessed using T cell activation assays. Bulk RNA sequencing and gene set enrichment analysis were performed on sorted DCs. Hypoxia was modeled in vitro, and HIF1α was perturbed using CRISPR-mediated knock-out. Results: ACT significantly increased survival but did not prevent tumor recurrence. Escaped tumors contained abundant cytotoxic, non-exhausted T cells, indicating that T cell dysfunction was not the primary driver of recurrence under ACT. Instead, tumor-associated DCs exhibited impaired T cell activation despite preserved antigen uptake. Transcriptomic analyses revealed reduced antigen presentation and co-stimulatory signaling, alongside increased expression of tolerogenic factors. ACT-treated tumors demonstrated heightened hypoxia pathway activation, with elevated HIF1α expression in DCs. Hypoxia induced DC tolerogenic programs and reduced their ability to activate T cells, an effect partially reversed by HIF1α disruption. Increased immune infiltration and inflammation following ACT further amplified hypoxia signaling and enhanced DC tolerance. Conclusions: DC dysfunction is one of the key mechanisms of immune escape following ACT in glioma. Hypoxia-driven tolerization of DCs impairs sustained anti-tumor immunity, highlighting the hypoxia–DC axis as a promising therapeutic target to enhance immunotherapy efficacy.

Myeloid-derived suppressor cells (MDSCs) are a class of immature, heterogenous, and functionally immunosuppressive myeloid progenitors that are expanded in malignant disease including glioblastoma (GBM). Extensive preclinical evaluation of GBM has revealed that MDSCs express multiple different chemokine and cytokine receptors that facilitate their entry, infiltration, expansion and immunosuppression of antitumor immunity in the tumor microenvironment. Additionally, translational investigation of approaches that target MDSCs directly or indirectly through immune remodeling has yielded promising effects that are under clinical trial investigation. Given the immunosuppressive phenotype of high-grade gliomas like GBM, the removal of MDSCs represents a clinically relevant strategy to enhance immune responses against neoplastic cells. In this review, we provide a comprehensive summary of MDSCs in GBM, emphasizing clinical observations and large-scale multi-omics studies that position MDSCs at the nexus of GBM immunosuppression. Next, we provide detailed coverage of multiple chemokines, cytokines, and growth factors that are relevant to MDSC migration, survival and expansion in GBM along with commentary on the associated receptors. Lastly, we discuss therapeutic approaches that directly target MDSCs as a strategy to improve immune responses against malignant brains and observations on the changes to MDSCs in the tumor microenvironment after immunotherapy. Our review serves as a valuable resource for the neuro-oncology research space, updating scientists and clinicians on a cell central to the biology and therapeutic targeting of GBM.