Tumor microenvironment-responsive nanocarriers for enhanced glioblastoma immunotherapy.

The glioblastoma (GBM) microenvironment exhibits a profoundly immunosuppressive state, which constitutes the major barrier limiting the efficacy of immunotherapy. It is intricately intertwined with aberrant physicochemical characteristics including severe hypoxia, acidic pH, and redox imbalance. Although these physicochemical abnormalities further exacerbate immunosuppression within the GBM microenvironment, they also paradoxically serve as precise endogenous triggers for designing smart nanocarriers. By exploiting these pathological features as triggering signals, microenvironment-responsive nanocarriers can overcome the physical barriers imposed by the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB), enabling precise delivery and on-demand release of immunomodulators at lesion site. Moreover, these nanocarriers can effectively alleviate immune tolerance by reprogramming tumor-associated immune cells or inducing immunogenic cell death, thereby remodeling the immunosuppressive GBM microenvironment. This review elucidates the physicochemical and immunosuppressive features of the GBM microenvironment. Furthermore, it systematically summarizes the design principles, cross-barrier targeting strategies, and immune remodeling mechanisms of responsive nanocarriers engineered upon tumor microenvironment (TME) characteristics. The analysis highlights the synergistic enhancement achieved through this paradigm: responding to TME signals to reverse immunosuppression. Finally, clinical translation challenges and future directions within this field are discussed to provide a comprehensive reference for designing highly efficient, GBM-targeted responsive nanoimmunotherapeutic platforms.