KS04.5.A ELECTRIC-FIELD-RESPONSIVE HYDROGEL FOR POSTOPERATIVE IMMUNOTHERAPY OF GLIOBLASTOMA RECURRENCE

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Abstract BACKGROUND Glioblastoma multiforme (GBM) represents a refractory malignancy of the central nervous system. Tumor Treating Fields (TTF) has emerged as a novel non-invasive treatment modality, yet its precise mechanism remains incompletely elucidated and clinical efficacy limited. The potential immunoregulatory properties of TTF suggest promising synergy with immunotherapeutic approaches for GBM management. MATERIAL AND METHODS C6 glioblastoma cells were exposed to TTF in vitro. Male Wistar rats and BALB/c mice were maintained under standardized conditions. Gene and protein expression were analyzed via RT-qPCR and Western blotting. Immunogenic cell death(ICD) markers were evaluated via calreticulin immunofluorescence and HMGB1 ELISA. Immune infiltration and tumor proliferation were characterized by flow cytometry and immunofluorescence. Hydrogels were formulated by combining 4 Arm-PEG-OPA with gelatin, incorporating gemcitabine to generate GAC@PG hydrogels. RESULTS TTF induced sphingolipid metabolism dysregulation in GBM cells, resulting in ceramide accumulation and consequent endoplasmic reticulum (ER) stress. This stress triggered ICD characterized by calreticulin translocation and ATP release. TTF significantly upregulated ceramide synthases while downregulating sphingomyelin synthases. Ceramide levels increased 2.1-fold (P<0.001), correlating with elevated ER stress markers including p-PERK (P=0.0001), cleaved ATF6 (P=0.00399), and CHOP (P=0.00152). TTF enhanced calreticulin exposure (1.8-fold, P=0.0051) and ATP release (1.5-fold, P<0.001), both attenuated by the ER stress inhibitor TUDCA. Our electric-responsive hydrogel (GC@PG) facilitated in situ CpG oligonucleotide delivery, enhancing antigen-presenting cell maturation. TTF+GC@PG co-treatment increased mature dendritic cells (1.46-fold, P=0.001) and macrophages (6.8-fold, P<0.001). In vivo, this combination significantly reduced tumor recurrence, extending median survival from 18.5 to >40 days (P=0.005). The treatment selectively depleted intratumor regulatory T cells (P<0.001). Additionally, CD8+ T cell infiltration increased substantially (P<0.001), accompanied by elevated pro-inflammatory cytokines IL-6 (3.2-fold, P=0.003) and IFN-γ (2.9-fold, P=0.002). CONCLUSION Our findings demonstrate that TTF activates sphingolipid metabolism and ER stress pathways to induce ICD. The developed electric-responsive hydrogels enhance antigen-presenting cell maturation and T cell activation, effectively reversing the immunosuppressive microenvironment and inhibiting postoperative GBM recurrence. This approach establishes a paradigm for integrating physical therapy with localized immunotherapy to overcome GBM-associated immunosuppression, offering a clinically translatable strategy for improving patient outcomes.

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