Abstract Glioblastoma remains uniformly lethal due to profound phenotypic plasticity and adaptive resistance. The proneural-to-mesenchymal transition (PMT) has emerged as a central axis functionally linking immune evasion, metabolic rewiring, and lineage remodeling. Relevant studies tend to interrogate the tumor microenvironment in a cell-type-specific manner, whereas accumulating evidence shows that PMT is not imposed by single populations but results from coordinated inputs of macrophages, T cells, neutrophils, astrocytes, and stromal partners through polarization dynamics, cytokine circuits (IL-6, TGF-β, IL-10), and metabolic modules (e.g. the lactate-HIF1a axis). Therapeutic strategies that distort this PMT-permissive ecosystem, including macrophage reprogramming (GM-CSF, CSF-1R blockade), immune checkpoint inhibition, metabolic targeting, and epigenetic modulation, have shown preliminary signals yet are constrained by redundancy, spatial heterogeneity, and compensatory feedback. This review reframes the immune microenvironment as a multicellular PMT-enforcing network, synthesizes cross-cell-type mechanistic evidence, and appraises translational attempts through the lens of PMT enforcement, while outlining opportunities such as biomarker-aligned stratification, spatial multi-omics guidance, and rational combinations designed to intercept PMT circuits. Anchoring therapeutic innovation in immune-driven PMT may provide a tractable entry to overcome resistance in glioblastoma.
Liu et al. (Wed,) studied this question.