Recurrent Glioblastoma and the Tumor Immune Landscape: Emerging Immunotherapeutic Strategies

Abstract: Glioblastoma (GBM) is the most aggressive malignant tumor affecting the central nervous system. Current standard of care provides only modest clinical benefits, most patients eventually develop tumor recurrence, at which point therapeutic options become markedly restricted and the prognosis remains dismal. In recent years, immunotherapy has achieved significant clinical success in several solid tumors and has become a key strategy for advanced cancers owing to its specificity and potent antitumor activity. Nevertheless, the immunosuppressive tumor microenvironment of recurrent GBM (rGBM), along with its pronounced heterogeneity, and the presence of blood-brain barrier collectively undermine the efficacy of immunotherapy. With increasing insights into the tumor microenvironment and immune escape mechanisms, alongside refinements in immunotherapeutic strategies, immunotherapy may ultimately become one of the therapeutic options for patients with rGBM. Currently, principal immunotherapies under investigation for rGBM include immune checkpoint inhibitors, CAR-T cell therapy, oncolytic virotherapy, and cancer vaccines. In this review, we comprehensively summarize the clinical evidence for these approaches, highlight their mechanisms of action, and critically evaluate the key challenges that limit clinical translation. By integrating recent therapeutic progress and unresolved obstacles, we aim to provide a timely perspective on the optimization of immunotherapy in rGBM and to inform the rational design of future clinical trials. Keywords: recurrent glioblastoma, immunotherapy, immune checkpoint inhibitors, CAR-T cell therapy, oncolytic virotherapy, cancer vaccines, tumor microenvironment