MALDI-TOF Mass Spectrometry for Glioblastoma Secretome Biomarker Screening: A Review of Challenges and Perspectives

Glioblastoma (GBM) remains one of the most aggressive malignancies, characterized by profound heterogeneity and a dismal prognosis. While genomic and transcriptomic profiling have provided structural insights, they often fail to capture the dynamic interactions within the tumor microenvironment (TME). Secretome analysis—the study of proteins actively secreted by tumor cells—offers a functional readout of these interactions and a reservoir for potential biomarkers. In this review, we critically evaluate the role of MALDI-TOF Mass Spectrometry as a strategic tool for GBM secretome profiling. While Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) remains the gold standard for deep protein discovery, we argue that MALDI-TOF’s speed, cost-effectiveness, and high-throughput capabilities position it as an ideal platform for clinical screening and “spectral phenotyping.” We discuss the technical hurdles, such as ion suppression and the “leakome” (intracellular contamination), and highlight how integrating MALDI with Extracellular Vesicle (EV) enrichment and Artificial Intelligence (AI) can bridge the gap between in vitro discovery and clinical application.