Tumor evasion of immune destruction is associated with the production of immunosuppressive
adenosine in the tumor microenvironment (TME). Anticancer
therapies can trigger
adenosine triphosphate (
ATP) release from
tumor cells, causing rapid formation of
adenosine by the ectonucleotidases CD39 and CD73, thereafter exacerbating immunosuppression in the TME. The goal of this study was to develop an approach to facilitate
cancer therapy-induced immunogenic cell death including
ATP release and to limit
ATP degradation into
adenosine, in order to achieve durable antitumor immune response. Our approach was to construct
reactive oxygen species (ROS)-producing nanoparticles that carry an ectonucleotidase inhibitor
ARL67156 by electronic interaction and phenylboronic
ester. Upon near-infrared irradiation, nanoparticle-produced ROS induced
ATP release from MOC1
cancer cells in vitro and triggered the cleavage of phenylboronic
ester, facilitating the release of
ARL67156 from the nanoparticles.
ARL67156 prevented conversion of
ATP to
adenosine and enhanced anticancer immunity in an MOC1-based coculture model. We tested this approach in mouse
tumor models. Nanoparticle-based ROS-responsive
drug delivery reprogramed the immunogenic landscape in
tumors, eliciting
tumor-specific T cell responses and
tumor regression, conferring long-term survival in mouse models. We demonstrated that TME reprograming sets the stage for response to anti-
programmed cell death protein 1 (PD1)
immunotherapy, and the combination resulted in
tumor regression in a 4T1
breast cancer mouse model that was resistant to PD1 blockade. Furthermore, our approach also induced immunological effects in patient-derived organotypic
tumor spheroid model, suggesting potential translation of our nanoparticle approach for treating human
cancers.