Decoding myeloid heterogeneity in glioblastoma: spatial insights from transcriptomics

Glioblastoma represents the most aggressive primary brain malignancy, characterized by a profoundly immunosuppressive microenvironment that limits therapeutic efficacy and drives disease progression. Myeloid cells—comprising tumor-associated macrophages, myeloid-derived suppressor cells, and dendritic cells—serve as central regulators of this milieu. However, their profound heterogeneity in origin, function, and localization has historically complicated efforts to neutralize their protumoral effects using conventional bulk analyses. This review synthesizes emerging insights from single-cell and spatial transcriptomics to decode myeloid dynamics across distinct glioblastoma anatomical compartments. We delineate how ontogeny and niche-specific cues sculpt cellular identity: microglia-derived macrophages predominate at the invasive leading edge to facilitate tumor dissemination, whereas monocyte-derived populations cluster in perivascular and necrotic zones to support angiogenesis and proliferation. Furthermore, the analysis highlights the hypoxic core as a critical niche where myeloid-derived suppressor cells and reprogrammed macrophages form immunosuppressive hubs, sequestering cytotoxic T cells and sustaining glioma stemness through specific signaling axes such as hypoxia-inducible factors and chemokine gradients. By mapping these spatially segregated mechanisms, this review offers a blueprint for next-generation precision oncology. Integrating spatial resolution into the understanding of myeloid heterogeneity supports a paradigm shift from uniform immunomodulation to niche-targeted interventions. Strategies that selectively disrupt compartment-specific interactions—ranging from invasion inhibitors at the periphery to metabolic modulators in the hypoxic core—hold the potential to dismantle the structural resilience of the glioblastoma microenvironment and overcome therapeutic resistance.