College
Morsani College of Medicine
Mentor Information
Emily Berger
Description
Glioblastoma (GBM) is one of the most aggressive brain tumors, with a median survival of approximately 15 months despite treatment and a recurrence rate near 90%. Therapeutic failure is largely driven by an immunosuppressive and therapy-resistant tumor microenvironment (TME). GBM progression depends on dysregulated receptor-mediated signaling pathways that regulate angiogenesis, immune evasion, stemness, metabolic adaptation, and phenotypic transition. Although targeting individual receptors has been explored, outcomes remain limited. This literature review evaluates how targeting receptor-mediated pathways—including neuromodulatory targets such as mGluR3—affects the TME and therapeutic response. It also compares the effectiveness of single versus multi-receptor targeting strategies. A PubMed search identified 33 peer-reviewed experimental studies and systematic reviews focused on GBM signaling pathways, tumor microenvironment interactions, and therapeutic targets. Findings indicate that receptor-specific interventions have distinct effects. VEGF inhibition reduces angiogenesis but may suppress immune activation. HRH1 blockade shifts tumor-associated macrophages toward a pro-inflammatory state and increases CD8+ T cell infiltration. Glioblastoma stem cells promote angiogenesis through histamine signaling via H1 receptors. GD2-directed CAR-T therapy enhances cytotoxic T cell activity while reducing immunosuppressive macrophages. Combined targeting of metabolic (GLUT1) and immune checkpoint (PD-1/PD-L1) pathways significantly improves immune response and survival in preclinical models. Overall, multi-target approaches are generally more effective than single-pathway strategies, though excessive pathway inhibition may increase toxicity. Targeting neuromodulatory receptors such as mGluR3 may offer a promising strategy to disrupt tumor-supportive signaling while preserving therapeutic balance.
How Do Different Receptor Targets in Glioblastoma Differentially Shape the Tumor Microenvironment and Influence Tumor Progression and Therapeutic Response?
Glioblastoma (GBM) is one of the most aggressive brain tumors, with a median survival of approximately 15 months despite treatment and a recurrence rate near 90%. Therapeutic failure is largely driven by an immunosuppressive and therapy-resistant tumor microenvironment (TME). GBM progression depends on dysregulated receptor-mediated signaling pathways that regulate angiogenesis, immune evasion, stemness, metabolic adaptation, and phenotypic transition. Although targeting individual receptors has been explored, outcomes remain limited. This literature review evaluates how targeting receptor-mediated pathways—including neuromodulatory targets such as mGluR3—affects the TME and therapeutic response. It also compares the effectiveness of single versus multi-receptor targeting strategies. A PubMed search identified 33 peer-reviewed experimental studies and systematic reviews focused on GBM signaling pathways, tumor microenvironment interactions, and therapeutic targets. Findings indicate that receptor-specific interventions have distinct effects. VEGF inhibition reduces angiogenesis but may suppress immune activation. HRH1 blockade shifts tumor-associated macrophages toward a pro-inflammatory state and increases CD8+ T cell infiltration. Glioblastoma stem cells promote angiogenesis through histamine signaling via H1 receptors. GD2-directed CAR-T therapy enhances cytotoxic T cell activity while reducing immunosuppressive macrophages. Combined targeting of metabolic (GLUT1) and immune checkpoint (PD-1/PD-L1) pathways significantly improves immune response and survival in preclinical models. Overall, multi-target approaches are generally more effective than single-pathway strategies, though excessive pathway inhibition may increase toxicity. Targeting neuromodulatory receptors such as mGluR3 may offer a promising strategy to disrupt tumor-supportive signaling while preserving therapeutic balance.
