Next-generation immunotherapy biologics for glioblastoma.

Glioblastoma (GBM) remains largely resistant to immunotherapy despite the success of immune checkpoint inhibitors in other solid tumors. Phase III trials have not demonstrated survival benefit for anti-PD-1 monotherapy, likely reflecting the GBM tumor microenvironment's profound myeloid-driven immunosuppression, low neoantigen burden, intratumoral heterogeneity, and adaptive resistance. These challenges have driven the development of next-generation immunotherapy biologics designed to reprogram the tumor microenvironment and overcome the innate and adaptive resistance of GBM. This review synthesizes advances in immunotherapy biologics including immune checkpoint combinations, cytokine and immunomodulatory proteins, adoptive cell therapies, vaccines, and oncolytic viruses, highlighting key preclinical insights and emerging clinical trial results. We conclude that improved tumor subtyping and immune profiling will be crucial to guide combination strategies that may achieve durable clinical benefit in GBM.