An inhalable nanoparticulate STING agonist synergizes with radiotherapy to confer long-term control of lung metastases

Yang Liu, William N. Crowe, Lulu Wang, Yong Lu, W. Jeffrey Petty, Amyn A. Habib and Dawen Zhao ()
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Yang Liu: Wake Forest School of Medicine
William N. Crowe: Wake Forest School of Medicine
Lulu Wang: Wake Forest School of Medicine
Yong Lu: Wake Forest School of Medicine
W. Jeffrey Petty: Wake Forest School of Medicine
Amyn A. Habib: University of Texas Southwestern Medical Center and VA North Texas Medical Center
Dawen Zhao: Wake Forest School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Mounting evidence suggests that the tumor microenvironment is profoundly immunosuppressive. Thus, mitigating tumor immunosuppression is crucial for inducing sustained antitumor immunity. Whereas previous studies involved intratumoral injection, we report here an inhalable nanoparticle-immunotherapy system targeting pulmonary antigen presenting cells (APCs) to enhance anticancer immunity against lung metastases. Inhalation of phosphatidylserine coated liposome loaded with STING agonist cyclic guanosine monophosphate–adenosine monophosphate (NP-cGAMP) in mouse models of lung metastases enables rapid distribution of NP-cGAMP to both lungs and subsequent uptake by APCs without causing immunopathology. NP-cGAMP designed for enhanced cytosolic release of cGAMP stimulates STING signaling and type I interferons production in APCs, resulting in the pro-inflammatory tumor microenvironment in multifocal lung metastases. Furthermore, fractionated radiation delivered to one tumor-bearing lung synergizes with inhaled NP-cGAMP, eliciting systemic anticancer immunity, controlling metastases in both lungs, and conferring long-term survival in mice with lung metastases and with repeated tumor challenge.

Date: 2019
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DOI: 10.1038/s41467-019-13094-5

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