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 therapies. Herein, we propose that magnesium hydride (MgH)-induced hydrogen (H) 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 H from MgH microspheres amplifies tumor cell destruction, thereby promoting immune cell recruitment to the tumor site. Meanwhile, the hydroxide ions (OH) and magnesium ions (Mg) generated by MgH 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 MgH therapy significantly enhances the anti-tumor efficacy of SDT compared to that of BTO alone, leading to prolonged survival of treated mice. Moreover, MgH 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.