Material-Encoded Synchronization of Immunogenic Cell Death With Adenosine A2A Receptor Blockade Reprograms the Tumor Microenvironment.

Adenosine rapidly suppresses antitumor immunity through the adenosine A2A receptor (A2AR). Immunogenic cell death (ICD) releases extracellular ATP, which can be rapidly converted into immunosuppressive adenosine. We therefore designed BSCS@PHY to synchronize ICD induction with local A2AR blockade in the same spatiotemporal window, aiming to protect antigen priming from adenosine-mediated suppression. BSCS@PHY integrates a bismuth-copper diselenide core for photothermal heating, glutathione depletion, and chemodynamic hydroxyl-radical generation; hyaluronic-acid-modified phase-change materials for on-site activation; the A2AR antagonist SCH442416 for local A2AR blockade; and yeast cell wall (YCW) components for innate adjuvanticity. Thermography-guided irradiation confines activation within a controlled window, melts the phase-change shell to expose the catalytic surface, and coordinates ICD amplification with co-localized A2AR blockade and dendritic-cell activation. In 4T1 tumors, BSCS@PHY enables image-guided activation, enhances ICD hallmarks, lowers adenosine signaling, promotes dendritic-cell maturation and T-cell priming, and improves tumor control, with additional benefit when combined with anti-PD-L1. Loss-of-function comparisons support nonredundant contributions of A2AR blockade and YCW-mediated adjuvanticity. This material-encoded strategy aligns danger-signal generation with local A2AR blockade in the same tumor niche and offers a framework for pairing ICD induction with metabolic-checkpoint control in cold tumors.