Smart Nano‐PROTACs Reprogram Tumor Microenvironment for Activatable Photo‐metabolic Cancer Immunotherapy

Abstract Protease inhibitors can modulate intratumoral metabolic processes to reprogram the immunosuppressive tumor microenvironment (TME), which however suffer from the limited efficacy and off‐targeted side effects. We report smart nano‐proteolysis targeting chimeras (nano‐PROTACs) with phototherapeutic ablation and cancer‐specific protein degradation to reprogram the TME for photo‐metabolic cancer immunotherapy. This nano‐PROTAC has a semiconducting polymer backbone linked with a cyclooxygenase 1/2 (COX‐1/2)‐targeting PROTAC peptide (CPP) via a cathepsin B (CatB)‐cleavable segment. CPP can be activated by the tumor‐overexpressed CatB to induce the degradation of COX‐1/2 via the ubiquitin‐proteasome system. The persistent degradation of COX‐1/2 depletes their metabolite prostaglandin E 2 which is responsible for activation of immune suppressor cells. Such a smart PROTAC strategy synergized with phototherapy specifically reprograms the immunosuppressive TME and reinvigorates antitumor immunity.