Targeting immune microenvironment-mediated mesenchymal transition in glioblastoma: Molecular mechanisms and...

Area of Science:

• Neuro-oncology
• Cancer immunology
• Cellular plasticity

Background:

• Glioblastoma (GBM) is a lethal brain tumor characterized by significant cellular plasticity and resistance to therapy.
• The proneural-to-mesenchymal transition (PMT) is a key mechanism underlying GBM's immune evasion, metabolic adaptation, and lineage plasticity.
• Current research often examines the tumor microenvironment (TME) in isolation, overlooking the coordinated cellular interactions driving PMT.

Purpose of the Study:

• To reframe the GBM immune microenvironment as a multicellular network that enforces PMT.
• To synthesize cross-cell-type mechanistic evidence linking immune cells and PMT.
• To critically evaluate therapeutic strategies targeting PMT within the GBM ecosystem.

Main Methods:

• Review and synthesis of existing literature on glioblastoma, PMT, and the tumor microenvironment.
• Analysis of cell-type-specific interactions, cytokine circuits (e.g., IL-6, TGF-β, IL-10), and metabolic pathways (e.g., lactate-HIF1α axis) involved in PMT.
• Appraisal of therapeutic interventions targeting the PMT-permissive ecosystem.

Main Results:

• PMT is orchestrated by coordinated inputs from diverse immune and stromal cells (macrophages, T cells, neutrophils, astrocytes).
• Therapeutic strategies targeting PMT (e.g., macrophage reprogramming, metabolic targeting) show promise but are limited by ecosystem redundancy and feedback.
• The GBM immune microenvironment functions as a complex, multicellular PMT-enforcing network.

Conclusions:

• Understanding the immune-driven PMT network is crucial for overcoming glioblastoma resistance.
• Future therapeutic strategies should focus on intercepting PMT circuits through rational combinations and patient stratification.
• Opportunities include biomarker-guided therapy, spatial multi-omics, and targeting synergistic interactions within the PMT network.