Glioma (GBM) is characterized by severe invasiveness and grim clinical outcomes. The therapeutic efficacy of conventional treatments is severely constrained by the blood-brain barrier (BBB), while the immunosuppressive tumor microenvironment (TME) further compromises treatment responsiveness. In GBM, abnormal expression of pyroptosis-related genes is closely associated with tumor malignancy and patient prognosis. Core pyroptosis-related genes were identified through bioinformatics screening. The active component arsenic trioxide (ATO) from traditional Chinese medicine was employed as a therapeutic agent, and it possesses unique advantages in inducing pyroptosis in tumor cells. Herein, we developed a brain-targeted biomimetic nanoplatform, termed As/ZIF-8@CM-RVG₂₉. The engineered nanoplatform exhibited efficient BBB penetration, enhanced tumor accumulation, and pH-responsive drug release. ATO triggered Caspase-3/GSDME-dependent pyroptotic cell death in glioma cells, remodeled the tumor immune microenvironment, and effectively suppressed orthotopic glioma growth. Furthermore, combination treatment with programmed cell death protein-1 (αPD-1) generated a synergistic antitumor response and significantly prolonged median survival in tumor-bearing mice. Collectively, these findings suggest a promising therapeutic strategy and provide evidence for the development of targeted immunotherapy against glioma.