Engineering of Immunoactive Hydrogels Complements Tumor-Treating Fields for Glioblastoma Therapy.

Abstract

Glioblastoma multiforme (GBM) as the most prevalent primary malignant brain tumor shows nearly universal recurrence following surgical resection. Tumor-treating fields (TTF), a promising and clinical therapy for GBM, may trigger antitumor immunity, as suggested by growing evidence. Herein, we uncover the TTF-triggered immunogenic cell death (ICD) at single-cell RNA sequencing resolution in GBM through sphingolipid-metabolism-associated pathway-mediated endoplasmic reticulum stress. Further, an ATP-responsive hydrogel adjuvant (Ha) was designed to synergize with TTF for spatiotemporally controlled release of antigens and CpG, reactivating myeloid cell interaction networks and augmenting sustained antitumor responses. The Ha-complemented TTF therapy (HaTTF) could effectively suppress tumor growth in GBM-bearing rats, outperforming TTF therapy, which merely delayed progression. This study establishes an adjuvant-enhanced tumoricidal immunity platform integrating TTF, with potential applications across various malignant solid tumors.