Magnesium hydride-induced hydrogen therapy for enhanced sonodynamic therapy†

The tumor microenvironment (TME) is typically immunosuppressive, playing a crucial role in tumor progression, immune evasion, and therapeutic resistance, all of which significantly impede the efficacy of cancer therapies¹. Herein, we propose that magnesium hydride (MgH₂)-induced hydrogen (H₂) therapy can synergistically enhance barium titanate (BTO)-mediated sonodynamic therapy (SDT) while modulating the TME to improve the efficacy of immune checkpoint inhibitors (aPD-1). Specifically, ultrasound (US) activated BTO to trigger SDT and induce immunogenic cell death (ICD), while the sustained release of H₂ from MgH₂ microspheres amplifies tumor cell destruction, thereby promoting immune cell recruitment to the tumor site. Meanwhile, the hydroxide ions (OH⁻) and magnesium ions (Mg²⁺) generated by MgH₂ alleviate the acidic TME, reversing immune suppression and enhancing T-cell-mediated antitumor responses. In the CT26 tumor model, the synergistic combination of SDT and MgH₂ therapy significantly enhances the anti-tumor efficacy of SDT compared to that of BTO alone, leading to prolonged survival of treated mice. Moreover, MgH₂ upregulates PD-1 expression in T cells, markedly improving the sensitivity of tumors to aPD-1 therapy. This strategy provides a generalizable approach for enhancing SDT, demonstrating its broad potential in anti-tumor treatment and presenting a promising avenue for overcoming resistance to immune checkpoint inhibitors.