Targeting the Negative Feedback of Adenosine‐A2AR Metabolic Pathway by a Tailored Nanoinhibitor for Photothermal Immunotherapy

The metabolite adenosine plays an important immunosuppressive role in the tumor microenvironment (TME) through its ligation with the metabolic checkpoint adenosine 2A receptor (A2AR). Here, an adenosine‐A2AR negative feedback pathway is highlighted during photothermal‐induced immunogenic cell death (ICD). Adenosine, hydrolyzed from ATP, is amplified during the photothermal‐induced ICD process. It is possible to achieve a robust ICD‐based immunotherapy via targeting the adenosine‐A2AR metabolic pathway. In this regard, an A2AR inhibitor‐loaded polydopamine nanocarrier masked by an acid‐sensitive PEG shell is designed to enable tumor‐specific delivery and photothermal‐induced ICD simultaneously. Upon reaching the acidic TME, the PEG shell selectively detaches and exposes the adhesive polydopamine layer, causing the inhibitors to accumulate at the tumor tissue. The accumulated inhibitors attenuate adenosine's metabolically suppressive effect and strengthen the ICD immune response. It occurs through promoting dendritic cell (DC) activation, increasing CD8+ T lymphocyte infiltration, and reducing the myeloid‐derived suppressor cell (MDSC) population. Furthermore, this synergistic therapy significantly regresses the primary tumor, inhibits distal tumor growth, and prevents lung metastasis. The study highlights a strategy to enhance the immunotherapy efficacy of ICD by blocking the metabolic checkpoint A2AR using advanced nanomaterials. In this study, the existence of the adenosine 2A receptor (A2AR) negative feedback pathway during photothermal therapy (PTT)‐induced immunogenic cell death (ICD) is validated. An A2AR inhibitor‐loaded polydopamine nanocarrier masked by an acid‐sensitive PEG shell is designed to simultaneously enable tumor‐specific inhibitor delivery and photothermal effect‐induced ICD. The strategy attenuates adenosine's metabolically suppressive effects and effectively strengthens the ICD immune response.