Immune Resistance in Glioblastoma: Understanding the Barriers to ICI and CAR-T Cell Therapy

Abstract

Background: Glioblastoma (GBM) is the most common primary malignant brain tumor, with fewer than 5% of patients surviving five years after diagnosis. The introduction of immune checkpoint inhibitors (ICIs), followed by chimeric antigen receptor (CAR) T-cell therapy, marked major advancements in oncology. Despite demonstrating efficacy in other blood and solid cancers, these therapies have yielded limited success in clinical trials for both newly diagnosed and recurrent GBM. A deeper understanding of GBM's resistance to immunotherapy is essential for enhancing treatment responses and translating results seen in other cancer models.

Objectives: In this review, we examine clinical trial outcomes involving ICIs and CAR-T for GBM patients and explore the evasive mechanisms of GBM and the tumor microenvironment.

Findings and discussion: Multiple clinical trials investigating ICIs in GBM have shown poor outcomes, with no significant improvement in progression-free survival (PFS) or overall survival (OS). Results from smaller case studies with CAR-T therapy have warranted further investigation. However, no large-scale trials or robust studies have yet established these immunotherapeutic approaches as definitive treatment strategies. Future research should shift focus from addressing the scarcity of functional T cells to exploiting the abundant myeloid-derived cells within the tumor microenvironment.

Conclusions: Translating these therapies into effective treatments for glioblastoma in humans remains a significant challenge. The highly immunosuppressive nature of GBM and its tumor microenvironment continue to hinder the success of these innovative immunotherapeutic approaches. Targeting the myeloid-derived compartment may lead to more robust and sustained immune responses.

Keywords: T cells; glioblastoma; immune microenvironment; neuroimmunology.

Figure 1

Schematic diagram illustrating how PD-1 and PD-L1 inhibitors prevent binding to their respective substrates, allowing the T cell to remain “on” and active in the fight against tumor cells. Created in BioRender. Suresh, R. (2025) https://BioRender.com/k07i775 (accessed on 18 January 2025).

Figure 2

Schematic diagram depicting the interaction between CTLA-4 and CD80, which delivers inhibitory signals that downregulate the T-cell immune response; thus, an anti-CTLA-4 antibody prevents this binding and keeps the T cell in a proactive, anti-tumor state. Created in BioRender. Suresh, R. (2025) https://BioRender.com/l15c497 (accessed on 18 January 2025).