# Decoding Glioblastoma Through Liquid Biopsy: Molecular Insights and Clinical Prospects

## TL;DR

Liquid biopsy methods like extracellular vesicles and ctDNA offer insights into glioblastoma's molecular changes and treatment response, with cerebrospinal fluid biomarkers showing higher sensitivity than plasma.

## Contribution

The paper highlights the complementary roles of various liquid biopsy components and emphasizes CSF-derived biomarkers and EVs for capturing tumor biology and resistance mechanisms in glioblastoma.

## Key findings

- CSF-derived biomarkers show higher sensitivity than plasma biomarkers for detecting glioblastoma alterations.
- EV-associated signatures correlate with tumor biology, therapy resistance, and immune evasion in glioblastoma.
- Combining ctDNA, EV-RNA, and circulating RNA profiling may improve liquid biopsy translation into clinical practice.

## Abstract

What are the main findings?
Extracellular vesicles, ctDNA, circulating RNA species, and CTCs provide complementary molecular information that reflects glioblastoma heterogeneity and treatment dynamics.CSF-derived biomarkers show consistently higher sensitivity than plasma biomarkers, while EV-associated signatures strongly correlate with tumor biology, therapy resistance, and immune evasion.

Extracellular vesicles, ctDNA, circulating RNA species, and CTCs provide complementary molecular information that reflects glioblastoma heterogeneity and treatment dynamics.

CSF-derived biomarkers show consistently higher sensitivity than plasma biomarkers, while EV-associated signatures strongly correlate with tumor biology, therapy resistance, and immune evasion.

What are the implications of the main findings?
Liquid biopsy can support diagnosis, early detection of recurrence and differentiation between progression and pseudoprogression when integrated with neuroimaging.Standardized multi-marker assays combining ctDNA, EV-RNA (Extracellular Vesicle RNA) and circulating RNA profiling may accelerate the translation of liquid biopsy into routine glioblastoma management.

Liquid biopsy can support diagnosis, early detection of recurrence and differentiation between progression and pseudoprogression when integrated with neuroimaging.

Standardized multi-marker assays combining ctDNA, EV-RNA (Extracellular Vesicle RNA) and circulating RNA profiling may accelerate the translation of liquid biopsy into routine glioblastoma management.

Liquid biopsy (LB) offers a minimally invasive approach to characterizing and monitoring glioblastoma (GB), a tumor marked by extensive heterogeneity, limited surgical accessibility and rapid molecular evolution. By analyzing circulating tumor-derived components such as circulating tumor DNA (ctDNA), extracellular vesicles (EVs), circulating RNA species and circulating tumor cells (CTC), LB provides dynamic molecular information that cannot be captured by neuroimaging or single-site tissue sampling. Cerebrospinal fluid (CSF) currently yields the highest sensitivity for detecting tumor-specific alterations, while plasma enables repeat monitoring despite lower biomarker abundance. EVs have gained particular prominence due to their ability to preserve DNA, RNA, and protein cargo that reflects key genomic changes, treatment resistance mechanisms, and immune evasion. Although advances are substantial, clinical implementation remains constrained by low analyte concentrations, methodological variability, limited standardization and the high cost of testing, which is rarely reimbursed by insurers. This review summarizes current evidence on circulating biomarkers in GB and highlights research priorities essential for integrating LB into future diagnostic and therapeutic workflows.