Cancer immunotherapy based on image-guided STING activation by nucleotide nanocomplex-decorated ultrasound microbubbles

Abstract

The cytosolic innate immune sensor cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is crucial for priming adaptive antitumour immunity through antigen-presenting cells (APCs). Natural agonists such as cyclic dinucleotides (CDNs) activate the cGAS-STING pathway, but their clinical translation is impeded by poor cytosolic entry and serum stability, low specificity, and rapid tissue clearance. Here, we developed an ultrasound (US)-guided cancer immunotherapy platform using nanocomplexes composed of 2’3’ cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) electrostatically bound to biocompatible branched cationic biopolymers that are conjugated onto APC-targeting microbubbles (MBs). The nanocomplex-conjugated MBs engaged with APCs and efficiently delivered cGAMP into the cytosol via sonoporation, resulting in activation of cGAS-STING and downstream proinflammatory pathways that efficiently prime antigen-specific T cells. This bridging of innate and adaptive immunity inhibited tumour growth in both localized and metastatic murine cancer models. Our findings demonstrate that targeted local activation of STING in APCs under spatiotemporally US stimulation results in systemic antitumour immunity and improves the therapeutic efficacy of checkpoint blockade, thus paving the way toward novel image-guided strategies for targeted immunotherapy of cancer.

Rational Nanomedicine Design Enhances Clinically Physical Treatment‐Inspired or Combined Immunotherapy

“…[111] Further, genetics regulation was harnessed to assist the ultrasound-guided immunotherapy especially after integrating with nanobiotechnology. Typically, Li et al designed ultrasound-guided immunotherapy nanocomplexes, [112] wherein the nanocomplexes were obtained based on ACPs-targeting microbubbles that were coated with 2′3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP)-adsorbed biopolymers. Through binding APCs, the loaded cGAMP was readily delivered into cytosol via microbubble cavitationenhanced membrane permeability to activate interferon-related cGAS-STING pathway and proinflammatory pathways and fur-ther stimulate antigen-specific T cells, which successfully connected innate and adaptive anti-tumor immunity to repress local and metastasized tumors especially after combining ICB immunotherapy.…”

Cancer Resistance to Immunotherapy: Molecular Mechanisms and Tackling Strategies

“…STING agonists have been used to provide clinical benefits; however, inefficient cytosolic entry and systemic toxicity are the main concerns of this strategy. To overcome these limitations, the microbubble-assisted ultrasound-guided immunotherapy of cancer (MUSIC) platform was developed, which inhibited tumor growth by bridging innate and adaptive immune responses in murine models [ 180 ]. Specifically, the nanocomplex-conjugated microbubbles that target APCs deliver cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) into the cytosol, where they induce a robust activation of STING and IFN regulatory factor 3 (IRF3) and activate downstream NF-κB signaling pathway.…”

“…This would stimulate APCs that subsequently prime CTLs. MUSIC can further sensitize poorly immunogenic tumors to PD-1 blockade by enhancing anti-tumor responses [ 180 ].…”

Ultrasound-guided medical procedures: a growing field with new opportunities

“…By combining different mechanisms of ultrasound (cavitation, acoustic streaming, ultrasound-induced vibration, acoustic scattering, and acoustic radiation forces) with creative system designs (e. g., bubble-based sensing, piezo-based sensing, nano-carriers, hydrogel carriers, sono-sensitizers, mechanosensitive proteins, fluid flow control, micro-and nano-robots) [36], unique capabilities have been realized for novel applications ranging from optical communication and imaging to targeted drug delivery and microsurgery [36,37]. A recent cutting-edge animal model study investigated a microbubble-assisted ultrasound-guided immunotherapy of cancer (MUSIC), using nanocomplex-conjugated microbubbles that target antigen-presenting cells to effectively deliver cyclic dinucleotides into their cytosol via ultrasound-guided sonoporation; this resulted in the activation of highly effective local and systemic antitumor immune responses [38]. Further of such ultrasound applications are in the pipeline.…”

“…B. bläschenbasierte Sensorik, piezobasierte Sensorik, Nanoträger, Hydrogelträger, Sono-Sensibilisatoren, mechanosensitive Proteine, Flüssigkeitsströmungs-Lenkung, Mikro-und Nanoroboter) [36] wurden einzigartige Möglichkeiten für neuar-tige Anwendungen geschaffen, die von optischer Kommunikation und Bildgebung bis hin zu gezielter Medikamentenabgabe und Mikrochirurgie reichen [36,37]. Eine aktuelle bahnbrechende Studie am Tiermodell untersuchte eine mikrobläschen-gestützte ultraschall-geführte Immuntherapie des Karzinoms (MUSIK), unter Verwendung von nanokomplex-konjugierten Mikrobläschen, die an antigen-präsentierende Zellen binden und via ultraschall-gezielte Sonoporation zyklische Dinukleotide in deren Zytosol abgeben; dies führte zur Aktivierung hocheffektiver lokaler und systemischer Immunreaktionen gegen den Tumor [38]. Weitere solcher Ultraschallanwendungen sind in der Entwicklung.…”