A Hybrid Cell Membrane-Based Vaccine Reprograms Macrophages and Modulates Tumor Microenvironment to Enhance Anti-Tumor Immunity and Prevent Glioblastoma Recurrence

Glioblastoma (GBM) relapse is fostered by a myeloid-dominant, immunosuppressed niche at the resection margin. We engineered an implantable postoperative depot that co-delivers hybrid membranes from GL261 tumor cells and M1 macrophages, CpG ODN, and local anti-CD47 within a calcium-alginate hydrogel. The hybrid vaccine was efficiently internalized, directly reduced GBM cell viability, and reprogrammed macrophages toward an M1 phenotype. Transcriptomics revealed coordinated upregulation of canonical glycolysis genes (HK1/HK2, PFKL, ALDOA, ENO1, LDHA), tightly correlated with M1 markers and glycolysis inhibition attenuated polarization, indicating a mechanistic coupling. In an orthotopic resection model, the depot provided sustained local release for ~2 weeks, markedly suppressed postsurgical regrowth. These data support a localized, systems-level strategy to limit GBM recurrence.