Glioblastoma (GBM) is the most aggressive primary brain tumor. This dataset contains label-free quantitative proteomic profiles of U87 human glioblastoma cells transduced with the optogenetic construct LOV2-STIM1-mCherry, comparing cells kept in the dark (CTL, n = 3 biological replicates) with cells subjected to 470 nm blue light stimulation (G, n = 3 biological replicates), acquired on a Bruker timsTOF mass spectrometer in data-independent acquisition (DIA) mode. The data support the finding that optogenetic CRAC channel activation induces NLRP3/caspase-1/GSDMD-mediated pyroptosis and inflammatory signaling in GBM cells, as described in the associated manuscript. Proteins with a fold change > 2 and P < 0.05 were considered differentially expressed and subjected to Gene Ontology enrichment analysis.