Common γ-chain cytokines in brain tumor immunotherapy: Biological barriers and advances in macromolecular delivery...

Brain tumors, particularly gliomas, remain a major therapeutic challenge due to their immunosuppressive microenvironment and resistance to immune infiltration. The immune-privileged status of the brain, maintained by the blood-brain barrier and reinforced by the blood-tumor barrier, restricts the entry of immune cells and therapeutic molecules. These barriers create an immune-excluded niche in which cytotoxic lymphocytes are unable to access and eliminate tumor cells, limiting the efficacy of immunotherapy. Cytokines, as regulators of immune communication and activation, offer a means to remodel the tumor microenvironment and re-establish antitumor immunity. However, their application in brain tumors is constrained by short half-life, rapid systemic clearance, off-target toxicity, and limited intratumoral retention. To overcome these challenges, delivery platforms, including nanoparticles, exosomes, and cell-based carriers, have been engineered to enhance cytokine stability, boost immune activation, improve tumor selectivity, and reduce systemic toxicity. These systems provide advantages, such as crossing biological barriers, sustaining localized cytokine bioactivity, and synergizing with immunotherapies to amplify therapeutic outcomes. These advances underscore the importance of delivery strategies in unlocking the therapeutic potential of cytokines for malignant brain tumors. The integration of biomaterials technology, immunoengineering, and synthetic biology is expected to drive the development of cytokine-based treatments.