Ultrasound-Targeted Microbubble Destruction: Modulation in the Tumor Microenvironment and Application in Tumor Immunotherapy

Abstract

Tumor immunotherapy has shown strong therapeutic potential for stimulating or reconstructing the immune system to control and kill tumor cells. It is a promising and effective anti-cancer treatment besides surgery, radiotherapy and chemotherapy. Presently, some immunotherapy methods have been approved for clinical application, and numerous others have demonstrated promising in vitro results and have entered clinical trial stages. Although immunotherapy has exhibited encouraging results in various cancer types, however, a large proportion of patients are limited from these benefits due to specific characteristics of the tumor microenvironment such as hypoxia, tumor vascular malformation and immune escape, and current limitations of immunotherapy such as off-target toxicity, insufficient drug penetration and accumulation and immune cell dysfunction. Ultrasound-target microbubble destruction (UTMD) treatment can help reduce immunotherapy-related adverse events. Using the ultrasonic cavitation effect of microstreaming, microjets and free radicals, UTMD can cause a series of changes in vascular endothelial cells, such as enhancing endothelial cells' permeability, increasing intracellular calcium levels, regulating gene expression, and stimulating nitric oxide synthase activities. These effects have been shown to promote drug penetration, enhance blood perfusion, increase drug delivery and induce tumor cell death. UTMD, in combination with immunotherapy, has been used to treat melanoma, non-small cell lung cancer, bladder cancer, and ovarian cancer. In this review, we summarized the effects of UTMD on tumor angiogenesis and immune microenvironment, and discussed the application and progress of UTMD in tumor immunotherapy.

Keywords: endothelial cells; tumor angiogenesis; tumor immunotherapy; tumor microenvironment; ultrasonic cavitation; ultrasound-targeted microbubble destruction.

Figure 1

(A) Schematic diagram of ultrasonic cavitation promoting DNA (green) extravasation into tissue. (B) Microjets generated by inertial cavitation creates acoustic pores that allow DNA to enter the cytoplasm. (C) Inertial cavitation increases the permeability of blood vessels to DNA by damaging the integrity of the vascular endothelium. Reprinted with permission from ref (13). copyright ^© 2012 Sirsi and Borden.

Figure 2

Effects of tumor cell death on tumor-associated antigen presentation. Tumor-associated antigens (TAA); dendritic cells (DC); major histocompatibility complex (MHC); damage-associated molecular pattern (DAMP); cytotoxic T lymphocytes (CTL); T regulatory cells (Treg); pattern recognition receptor (PRR); T-cell receptor (TCR); helper T cell (Th); tumor necrosis factor (TNF); programmed cell death protein 1 (PD-1); programmed cell death-ligand 1 (PD-L1). Reprinted with permission from ref (69). copyright ^© 2020 de Souza, Gonçalves, Lepique and de Araujo-Souza.

Figure 3

Schematic illustration showing the effects of ultrasound-stimulated nanobubbles (USNBs) on the mouse tumor model. USNBs can induce tumor cell necrosis, which can release immunogenic substances, further activate innate and adaptive immune cells, and finally activate CD8+ T cells. This leads to systemic anti-tumor immunity, enhancing the efficacy of anti-PD1 therapy and promoting immune memory. Reprinted (adapted) with permission from ref (18). copyright ^© 2022 Hu, He, Wang, Zhao, Fang, Dong, Chen, Zhang, Zhang, Wang, Tan, Wang, Zi, Liu, Liang, Guo, Ou.

Figure 4

Ultrasound microbubbles mediated sonosensitizer and trastuzumab (TP MBs) treatment significantly inhibited the proliferation of tumor cells. The TP MBs + US group showed the best therapeutic effect with almost no tumor volume change for 21 days. Reprinted (adapted) with permission from ref (20). copyright ^© 2022 American Chemical Society. **p<0.01.