Antitumor Effects of a Distinct Sonodynamic Nanosystem through Enhanced Induction of Immunogenic Cell Death and Ferroptosis with Modulation of Tumor Microenvironment

[Image: see text] Sonodynamic therapy (SDT) holds great promise to be applied for cancer therapy in clinical settings. However, its poor therapeutic efficacy has limited its applications owing to the apoptosis-resistant mechanism of cancer cells. Moreover, the hypoxic and immunosuppressive tumor microenvironment (TME) also weakens the efficacy of immunotherapy in solid tumors. Therefore, reversing TME remains a formidable challenge. To circumvent these critical issues, we developed an ultrasound-augmented strategy to regulate the TME by utilizing an HMME-based liposomal nanosystem (HB liposomes), which can synergistically promote the induction of ferroptosis/apoptosis/immunogenic cell death (ICD) and initiate the reprograming of TME. The RNA sequencing analysis demonstrated that apoptosis, hypoxia factors, and redox-related pathways were modulated during the treatment with HB liposomes under ultrasound irradiation. The in vivo photoacoustic imaging experiment showed that HB liposomes enhanced oxygen production in the TME, alleviated TME hypoxia, and helped to overcome the hypoxia of the solid tumors, consequently improving the SDT efficiency. More importantly, HB liposomes extensively induced ICD, resulting in enhanced T-cell recruitment and infiltration, which normalizes the immunosuppressive TME and facilitates antitumor immune responses. Meanwhile, the HB liposomal SDT system combined with PD1 immune checkpoint inhibitor achieves superior synergistic cancer inhibition. Both in vitro and in vivo results indicate that the HB liposomes act as a sonodynamic immune adjuvant that is able to induce ferroptosis/apoptosis/ICD via generated lipid-reactive oxide species during the SDT and reprogram TME due to ICD induction. This sonodynamic nanosystem integrating oxygen supply, reactive oxygen species generation, and induction of ferroptosis/apoptosis/ICD is an excellent strategy for effective TME modulation and efficient tumor therapy.