Residual Glioma Stem Cells and the Post-surgical Microenvironment in Glioblastoma Recurrence: Mechanistic Basis and Therapeutic Potential of Chinese Herbal Medicines and Natural Products

Abstract

Standard treatment for glioblastoma (GBM) combines maximal safe resection, radiotherapy, and temozolomide, yet recurrence remains common and is usually detected near the resection cavity. Longitudinal single-cell studies, paired primary-recurrent tumor analyses, and resection models indicate that recurrence reflects more than the persistence of infiltrating tumor cells; it also involves therapy-induced cell-state transitions and post-surgical tissue repair. Residual glioma stem cells (GSCs) may survive treatment through quiescent or slow-cycling states, enhanced DNA damage responses, metabolic reprogramming, and phenotypic plasticity. Reactive astrocytes, immunosuppressive myeloid cells, extracellular matrix remodeling, and changes in vascular barrier function may further support residual-cell survival and regrowth. This narrative review examines the interaction between residual GSCs and the post-surgical microenvironment and evaluates evidence for Chinese herbal formulations and natural products that affect GSC stemness, ferroptosis, proteostasis, inflammatory and immune signaling, or local drug delivery. Current evidence is derived predominantly from in vitro and animal studies, and no clinical study has established that these interventions prevent post-surgical recurrence in patients with GBM. Future work should use immunocompetent models that incorporate resection and standard chemoradiotherapy and should establish quantitative relationships among local exposure, pharmacodynamic biomarkers, formulation quality, and safety in normal brain tissue.