Magnesium-Enhanced Magnetic Hyperthermia for Triggering Vaccine-Like Antitumor Immunotherapy.

Abstract

Cancer immunotherapies, such as programmed cell death protein 1 (PD-1) inhibitors, cancer vaccines, and chimeric antigen receptor T cells (CAR-T cells), have become first-line treatments for multiple tumors by eliciting antitumor immunity. However, their limited efficacy in immunosuppressive tumors, particularly Head and Neck Squamous Cell Carcinoma (HNSCC), underscores the urgent need for versatile therapeutics. Hereinto, we develop an injectable hydrogel incorporating Mg microparticles and Fe₃O₄ magnetic nanoparticles (Mg/Fe₃O₄@Gel) to enhance antitumor immunotherapy, achieving potent vaccine-like tumor suppression against both distant and newly emerging tumors. Under an alternating magnetic field, Mg/Fe₃O₄@Gel induces HNSCC cell death via magnetic hyperthermia, while simultaneously triggering mitochondrial dysfunction and disrupting redox homeostasis, resulting in a 72% apoptosis rate. Meanwhile, the released corrosion products effectively neutralize the intracellular acidic environment, further enhancing the efficacy of systemic immunotherapy. Mechanistic studies induce Mg/Fe₃O₄@Gel immunogenic cell death via Ltf regulation, facilitating effective eradication of both primary and distant lesions. Moreover, vaccination with Mg/Fe₃O₄@Gel-killed tumor cells and adoptive CD3⁺ T cell transfer confer robust antitumor immunity, achieving 80% tumor growth suppression in immunodeficient models and surpassing typical clinical outcomes. Overall, our study highlights the potential of this metal-based hydrogel as a universal platform to enhance antitumor efficacy through a synergistic immunotherapeutic strategy.