Stem Cell-Based Delivery of Immunomodulators for Overcoming Glioblastoma Immune Evasion

Glioblastoma (GBM) is the most aggressive primary brain tumour in adults, characterised by rapid progression, extensive heterogeneity, and poor outcomes despite surgery, radiotherapy, and temozolomide (TMZ). A subpopulation of glioblastoma stem cells (GSCs) with self-renewal and multi-lineage differentiation capabilities drives tumour initiation, progression, recurrence, and therapeutic resistance. GSCs evade conventional treatments via enhanced DNA repair, multidrug efflux, activation of survival pathways, epigenetic reprogramming, and entry into quiescent states. Moreover, these cells utilise key immune escape mechanisms, such as downregulation of major histocompatibility complex molecules and the secretion of immunosuppressive factors, to escape detection and destruction by the immune system. Evidence suggests that transformed neural stem cells are a likely source of GSCs, with key survival networks including EGFR, FGFR, HGFR, and PI3K/AKT/mTOR signalling. Their phenotypic plasticity and adaptability to the tumour microenvironment further complicate eradication. Stem cell-based strategies utilising NSCs, MSCs, haematopoietic stem/progenitor cells, or induced pluripotent stem cells can effectively deliver immunomodulators to counteract these immune evasion mechanisms, exploiting tumour tropic migration to deliver therapeutic payloads into hypoxic and infiltrative niches. Approaches such as suicide gene therapy, oncolytic virus delivery, and CXCL12-CXCR4 axis modulation aim to target both proliferative and dormant GSCs. Preclinical studies demonstrate promising efficacy, yet challenges remain, including safety concerns, variability in outcomes, and the limited translational relevance of current models. This review provides a concise overview of GSC biology, resistance mechanisms, and emerging stem cell-based interventions, highlighting opportunities and obstacles in developing effective therapies for GBM.