Glioblastoma (GBM) persists as one of the greatest challenges in the treatment of human cancer, despite extensive efforts to leverage the therapeutic potential of immunotherapy. While checkpoint blockade and other forms of immunotherapy have revolutionized the treatment of various cancers, their therapeutic efficacy in GBM has been hindered by the profound immunosuppressive environment, spatial heterogeneity, and dynamic immune metabolic challenges associated with the tumor microenvironment. In this review, we will synthesize recent advances and insights to develop a next-generation framework for GBM immunotherapy based on systems biology approaches to understanding the complex interplay between GBM and the immune system, as opposed to single-axis approaches to immune activation and modulation. We will discuss how the functional competence of the interferon system, myeloid antigen presentation status, T-cell clone status, spatial organization of the immune microenvironment, and resource competition between GBM and the immune system dictate therapeutic responsiveness. Furthermore, the current paper elucidates how recent advances in spatial transcriptomics, single-cell analysis, and high-parameter imaging enable us to understand how immune phenotype status varies across GBM regions and treatment status, and how this information can be used to develop predictive and pharmacodynamic biomarkers of therapeutic efficacy and failure. We will then discuss how these advances form the basis for rational combination approaches to GBM immunotherapy, which involve the integration of checkpoint blockade with metabolic reprogramming, myeloid modulation, and interferon system reactivation, and how artificial intelligence-based analytics and adaptive clinical trial design can guide the development of biomarker-based therapeutic selection approaches.
Poe et al. (Fri,) studied this question.
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