Spatiotemporal-heterogeneity originating from genomic and transcriptional variation contributes to subtype switching in GBM prior to and upon recurrence. Fluorescence-guided neurosurgical resection utilizing 5-aminolevulinic acid (5ALA) enables the isolation of infiltrative margin tumor cells (5ALA+) from a non-neoplastic background within neighboring brain parenchyma. Spatial transcriptomics identifies GBM molecular subtype plasticity as not restricted to recurrence, but manifesting regionally in a cell-type-specific manner, where a 5ALA+ Mesenchymal subtype may drive recurrence. Exon-intron split analysis reveals hijacking of the neural wound response pathway to promote tumor growth, via IRF8-mediated post-transcriptonal control. A unique stemness index further defines 5ALA+ cells as a rare sub-population of infiltrative GBM stem cells. Finally, we establish that enriched gene signatures of 5ALA+ cells are associated with poor survival and recurrence in GBM, signifying that transition from primary to recurrent GBM is not discreet, but rather a continuum whereby 5ALA+ residual disease more closely resembles the eventual recurrent GBM.