Boosting Cancer Immunotherapy via the Convenient A2AR Inhibition Using a Tunable Nanocatalyst with Light-Enhanced Activity.

ABSTRACT

Blockade of A2A adenosine receptors (A2AR)-adenosinergic signaling shows high potency to mobilize antitumor immunity for its in-depth involvement in immune regulation of nearly all immune cells. Available A2AR inhibition strategies are mainly based on small molecules or proteins inhibitors, yet are limited by the non-specific operation as well as the off-target toxicity. Herein, the first effort to design a convenient tumor-specific A2AR inhibition strategy to improve antitumor immune responses via the spatiotemporally controlled oxygen supply by virtue of a versatile photo-modulated nanoreactor is reported on. This nanoreactor, consisting of a catalase-mimicking shell (Pt nanocatalyst) and a photothermal core (polydopamine), is rationally designed for achieving the near-infrared radiation (NIR)-guided/accelerated oxygen supplementation on tumor site, and for relieving the A2AR-mediated immunosuppression without toxicity concern. Meanwhile, the NIR light could also mediate the direct photothermal ablation of tumor, and elicit immunogenic cell deaths to boost antitumor immunity. In a poorly immunogenic breast cancer model, the intravenous injection of the nanoreactor leads to the improved immune response with an increased animal survival rate, and achieves the long-term immunological memory effect against tumor recurrence as well as rechallenge. This convenient nanoreactor-stimulated A2AR inhibition approach provides a versatile promising paradigm for improving these existing immunotherapies.