Pro- and Anti-tumorigenic Effects of MSC Secretome in Glioblastoma: Mechanisms and Therapeutic Implications.

Despite advances in surgical resection, radiation, and chemotherapy, glioblastoma remains a lethal condition driven by intrinsic heterogeneity, therapy resistance, and an immunosuppressive tumour microenvironment. Mesenchymal stromal cells (MSCs) and their secretomes, comprising cytokines, growth factors, and extracellular vesicles, have emerged as promising therapeutic candidates due to their tumour-homing properties and anti-inflammatory and immunomodulatory potential. However, recent evidence reveals a paradox: MSC secretomes exhibit both anti-inflammatory/immunomodulatory potential and pro-tumorigenic activities, depending on MSC source, passage number, and environmental and manufacturing contexts. In this review, we critically examine the molecular mechanisms underlying these opposing effects, synthesising evidence on how MSC source, donor variability, passage number, and environmental priming/licensing (e.g., hypoxia, inflammatory licensing) dictate secretome composition and function. We identify critical manufacturing determinants, including the necessity for upper passage limits and standardised isolation protocols, and propose a translational framework that integrates mechanism-based potency assays, such as nuclear factor-κB (NF-κB) reporter systems and multi-donor mixed lymphocyte reactions, to predict clinical activity. Establishing these robust quality controls and mechanistic release and rejection criteria will be essential to resolve the functional plasticity of secretomes and enable the safe translation of MSC-based therapies for glioblastoma.