Mechanisms underlying the failure of PD-1/PD-L1 blockade in glioblastoma: Therapeutic challenges and opportunities

Abstract

Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis and limited therapeutic options. Although programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade has transformed the treatment of several malignancies, its clinical benefit in GBM remains limited, and the mechanisms underlying this resistance remain poorly understood.​ This review summarizes the biological roles of the PD-1/PD-L1 axis in the GBM microenvironment, evaluates clinical evidence for immune checkpoint inhibitors, and discusses mechanisms of resistance and strategies to overcome therapeutic resistance.​ It integrates current preclinical and clinical evidence on PD-1/PD-L1 signaling, the cellular sources of PD-L1, clinical trial outcomes, resistance mechanisms, and emerging combination strategies.​ We propose a dual-source PD-L1 framework to discuss the potential contributions of tumor cell-derived and immune cell-derived PD-L1 to GBM-mediated immunosuppression and therapeutic response. However, whether these two PD-L1 sources have distinct functional specializations remains unproven and requires further validation through spatial omics analyses and cell-type-specific functional studies. This framework may help explain the limited value of total PD-L1 expression as a single predictive biomarker in GBM. We further outline a multilayer resistance model involving the blood–brain barrier, an immunologically cold tumor microenvironment, and compensatory immunosuppressive networks. Emerging strategies, including optimized treatment timing, microenvironmental modulation, and rational immunotherapy combinations, are also discussed.​ A deeper understanding of PD-1/PD-L1 biology and multilayered immune resistance may guide the development of more effective immunotherapeutic strategies for GBM.