Nanodroplet-enhanced sonodynamic therapy potentiates immune checkpoint blockade for systemic suppression of triple-negative breast cancer

Immune checkpoint blockade (ICB) has shown great promise in treating various advanced malignancies including triple-negative breast cancer (TNBC). However, only limited number of patients could benefit from it due to the low immune response rate caused by insufficient matured dendritic cells (DCs) and in-adequate tumor infiltration of cytotoxic T lymphocytes (CTLs). Here, we report a combination therapeutic strategy which integrates STING pathway activation, hypoxia relief and sonodynamic therapy (SDT) with anti-PD-L1 therapy to improve the therapeutic outcome. The synthesized nanodroplet consisted of a O2- filled Perfluorohexane (PFH) core and a lipid membrane carrying sonosensitizer IR-780 and STING agonist Vadimezan (DMXAAs). It released O2 inside the hypoxic tumor tissue, thereby enhancing SDT which re-lied on O2 to generate cytotoxic reactive oxygen species (ROS). The co-delivered STING agonist DMXAAs promoted the maturation and tumor antigen cross-presenting of DCs for priming of CTLs. Moreover, SDT induced immunogenic cell death (ICD) of tumor to release abundant tumor-associated antigens, which increased tumor immunogenicity to promote tumor infiltration of CTLs. Consequently, not only a robust adaptive immune response was elicited but also the immunologically cold TNBC was turned hot to enable a potent anti-PD-L1 therapy. The nanodroplet demonstrated strong efficacy to systemically sup-press TNBC growth and mimic distant tumor in vivo. Statement of significance Only a limited number of triple-negative breast cancer (TNBC) patients can benefit from immune check-point blockade therapy due to its low immune response rate caused by insufficient matured DCs and inadequate tumor infiltration of cytotoxic T lymphocytes (CTLs). Interestingly, compelling evidence has shown that sonodynamic therapy (SDT) not only directly kills cancer cells but also elicits immunogenic cell death (ICD), which promotes tumor infiltration of cytotoxic T lymphocytes to transform an immuno-suppressive cold tumor into a hot one. However, the hypoxic tumor microenvironment severely re-stricts the therapeutic efficiency of SDT, wherein, oxygen is indispensable in the process of ROS genera-tion. Here, we report an O2-filled nanodroplet-enhanced sonodynamic therapy that significantly potenti-ated immune checkpoint blockade for systemic suppression of TNBC. (c) 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Automated summary

A combination therapeutic strategy integrating STING pathway activation, hypoxia relief, and sonodynamic therapy (SDT) with anti-PD-L1 therapy was reported to improve the therapeutic outcome in triple-negative breast cancer (TNBC). The synthesized nanodroplet released oxygen and promoted SDT to generate cytotoxic reactive oxygen species (ROS), while the co-delivered STING agonist promoted the maturation and tumor antigen cross-presenting of dendritic cells (DCs) for priming of cytotoxic T lymphocytes (CTLs). Additionally, SDT induced immunogenic cell death (ICD) and increased tumor immunogenicity to promote tumor infiltration of CTLs.