Decoding PD-1 Resistance: From Microenvironment to Combination Therapies in Glioblastoma

Glioblastoma (GBM) is one of the most aggressive malignant brain tumors. The Stupp protocol is associated with a short median survival and high recurrence rate, referring to limited effective therapeutic alternatives. Various immunotherapies are therefore under active investigation. However, to date, their clinical application has been hindered by an unfavorable risk-benefit profile, with drug resistance posing a major barrier to therapeutic success. This review focuses on an immune checkpoint PD-1/PD-L1 inhibitors, which have shown limited efficacy as monotherapy. Key mechanisms of resistance include the immunosuppressive tumor microenvironment, aberrant genetic and epigenetic regulation, and impaired T-cell function and infiltration. To address these challenges, combination strategies targeting these resistance mechanisms have been developed, including combination of dual or triple drug regimens, targeting multiple pathways to reverse the immunosuppressive tumor microenvironment or correct underlying genetic abnormalities, along with the optimization of drug delivery routes to fundamentally enhance the drug efficacy. These approaches offer a promising theoretical framework for enhancing the therapeutic efficacy of immune checkpoint inhibitors in GBM.