Synergistic SDT/cuproptosis therapy for liver hepatocellular carcinoma: enhanced antitumor efficacy and specific mechanisms

The efficacy of sonodynamic therapy (SDT), an emerging approach for tumor treatment, is hindered by the high levels of the antioxidant glutathione (GSH) in the tumor microenvironment (TME). In this study, we constructed nanobubbles loaded with the sonosensitizer HMME and the tumor-targeting peptide RGD (HMME-RGD@C₃F₈ NBs) for synergistic SDT/cuproptosis therapy of liver hepatocellular carcinoma (LIHC) in combination with Elesclomol-Cu as cuproptosis inducers. Endogenous GSH is consumed by Cu²⁺ to modulate the complex TME, thereby amplifying oxidative stress and further improving SDT performance. Additionally, intracellular Cu²⁺ overload can induce cuproptosis, which is further amplified by SDT, to initiate irreversible protein toxicity. The specific mechanism of synergistic SDT/cuproptosis therapy in LIHC was investigated by RNA sequencing analysis. The synergistic SDT/cuproptosis therapy reprogrammed the TME to improve the efficacy of immune checkpoint inhibitor-based immunotherapy. Furthermore, a risk-scoring model was created and displayed significant promise in the prognosis of LIHC.