Overcoming Tumor Hypoxia and Adenosine‐mediated Immunosuppression for Boosting Photodynamic Therapy and Systemic Antitumor Immune Responses

Photodynamic therapy (PDT)‐induced immunogenic cell death (ICD) is an important approach for enhancing in situ tumor immunogenicity and activating systemic immune response. However, the tumor immunosuppressive microenvironment often limits the immunotherapeutic effect of single‐modal PDT. Notably, the adenosine‐A2A receptors (A2AR)‐related signal pathway plays a key role in tumor immunosuppression. Herein, we report a multifunctional nanoplatform (SPN S ) for the targeted delivery of mimetic enzyme (Hemin), photosensitizers (PCPDTBT) and A2AR inhibitor (SCH58261) cancer cells. This platform aims to overcome tumor hypoxia and adenosine‐mediated immunosuppression, thereby further improving the PDT‐immunotherapy efficacy. In vitro and in vivo results demonstrate that our SPN S can synergistically regulate tumor immunosuppression through a combination of oxygen supply (enhancing PDT efficacy and alleviating A2AR‐mediated inhibition), ICD‐induced tumor immunogenicity (via PDT), and direct A2AR blockade (using an A2AR antagonist). After intravenous injection of SPN S and then phototherapy in vivo, the alleviated hypoxia microenvironment and adenosine‐mediated immunosuppression can lead to amplifying ICD‐induced immune responses. This is accompanied by enhanced DC maturation, increased tumor infiltration of immune effector cells and elevated secretion of antitumor cytokines. This work highlights that the synergistic regulation of tumor immunosuppression is an effective therapeutic strategy to inhibit tumor growth and suppress metastasis.