A pH‐Sensitive Nanosized Covalent–Organic Polymer for Enhanced Tumor Photodynamic Immunotherapy by Hypoxia Relief and STAT3 Inhibition

Photodynamic therapy (PDT) is a promising cancer therapy modality by generating reactive oxygen species (ROS) and triggering immunogenic cell death. However, the therapeutic effect of PDT is strongly limited by tumor hypoxia and immunosuppressive landscape. Herein, a pH-sensitive nanosized covalent-organic polymer (COP), composed of the photosensitizer porphyrin and pyruvate kinase inhibitor vitamin K3 (VK3), is designed to overcome these issues. The signal transducer and activator of transcription 3 (STAT3) inhibitor WP1066 is further encapsulated into COPs to form a WP1066-loaded COP (TVW). As an inhibitor of pyruvate kinase, VK3 can reduce intracellular oxygen consumption by inhibiting the glycolytic pathway, leading to the alleviation of the tumor hypoxic microenvironment. The relief of tumor hypoxia by VK3 enhances photodynamic cytotoxicity by generating more ROS. Meanwhile, STAT3 acts as a major regulator of PD-L1, a key inhibitor that promotes immune escape. WP1066 effectively inhibits the expression of STAT3 and reduces PD-L1 expression, thereby significantly inhibiting tumor immune escape and enhancing antitumor efficacy in a synergistic manner. The antitumor capacity of photodynamic immunotherapy is extensively investigated in a murine subcutaneous hepatocellular carcinoma model. This photo-immunotherapy may provide an effective combination regimen for the efficient treatment of solid tumors such as hepatocellular carcinoma.