Amplifying oxidation stress and T-cell activation by bioactive layered double hydroxide sonosensitizers for enhanced cancer immunotherapy

Sonodynamic therapy (SDT) is a potential non-invasive therapeutic to overcome the limitation of depth and to enhance immunotherapy by converting "cold" to "hot" tumors. However, the intervention effect of SDT-induced hot tumors may not be sufficient to effectively enhance the effect of immunotherapy due to the intricate tumor microenvironment (TME). Herein, a multifunctional and potent sonosensitizer based on layered double hydroxides (LDHs) with a suitable bandgap and diverse immunological effects (activation of T cells and enhancement infiltration of T cells) was designed to facilitate high-performance SDT combined with immunotherapy. Briefly, Ca2+ was introduced into MgFe-LDH to construct MgCaFe-LDH to achieve excellent SDT performance, outstanding modulated TME ability, and a tremendous prognosis effect. The better SDT efficiency was attributed to the optimized electron structure and bandgap with increasing Ca2+ introduction. The regulation of the intricate TME by improving the hypoxic microenvironment and decreasing the concentration of glutathione (GSH) with reducibility to enhance oxidation stress further boosted the SDT effect. In addition, bioactive MgCaFe-LDH exhibited an excellent immunological function, resulting from Mg2+ and Ca2+ ions synergistically activating CD8+ and CD4+ T cells and enhancing the infiltration of T cells into tumor tissues. Moreover, the combined therapy with SDT and αCTLA-4 also displayed a suppressive effect on the bilateral tumor model. Our work highlights novel bioactive LDH sonosensitizers that integrate TME regulation, SDT, and immunological effects for efficient cancer therapy.