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.