ROS‐Activatable Cyclodextrin Nanoparticles Remodel Adenosine‐A2AR Pathway for Augmented Photo‐Immunotherapy

Abstract Massive ATP secretion during photodynamic therapy (PDT) can rapidly degrade into immunosuppressive adenosine (ADO), thus offsetting or even exacerbating anti‐tumor immunity. Delivering ADO‐modulating agents can relieve this immunosuppression, but the dose‐dependent adverse effects and non‐selective inhibition in normal tissues limit their clinical use. In this study, a supramolecular nanoparticle (CTV) based on noncovalent host‐guest recognition between chlorin e6‐modified β‐cyclodextrin and amantadine‐terminated ADO A2A receptor (A2AR) antagonist vipadenant via a ROS‐activatable linker is constructed. Under photo‐irradiation, the CTV ignites the immunogenic cell death (ICD) of tumor cells, while in situ photo‐activation and release of vipadenant effectively blocks ADO‐A2AR interaction. The combination altogether sustains cytotoxic T cell functions and downregulates regulatory T cell activities, resulting in efficient primary tumor and metastasis inhibition. Collectively, such a simple but activatable nanoparticle is presented as a paradigm in synergistic photo‐immunotherapy.