Targeting taurine metabolism via PROTAC-mediated SLC6A6 degradation potentiates photodynamic therapy and reverses immunosuppression in cholangiocarcinoma

BACKGROUND: Photodynamic therapy (PDT) is a promising treatment for cholangiocarcinoma (CCA), but its efficacy is limited by robust tumor antioxidant defenses and immunosuppressive microenvironment. Disrupting the expression of SLC6A6, a taurine transporter critical for redox homeostasis, represents a promising strategy for sensitizing CCA cells to PDT by disrupting taurine-mediated antioxidant protection. METHODS: A first-in-class antibody-based PROTAC (AbTAC) specifically targeting SLC6A6 degradation was developed, followed by the engineering of biomimetic, ROS-responsive nanoparticles cloaked with CCA cell membranes (CM-TAC@Ce@PEG) for tumor-targeted co-delivery of the AbTAC and the photosensitizer chlorin e6 (Ce6). Comprehensive nanoparticle characterization covered size, drug loading, spectral properties, ROS production, and drug release kinetics. And the CM-TAC@Ce@PEG was evaluated for targeted fluorescence imaging and therapeutic efficacy in vitro and in vivo, with further investigation of its synergy with anti-PD-1 immunotherapy. RESULTS: Preclinical studies demonstrated that light-induced ROS triggers nanoparticle depolymerization. SLC6A6 degradation depletes taurine in tumor cells, disrupting antioxidant defenses and inducing ferroptosis. Crucially, CM-TAC@Ce@PEG simultaneously induces tumor cells to secrete colony-stimulating factor 2 (CSF2), driving M1 macrophage polarization and restoring CD8⁺ T cell cytotoxicity. This dual action powerfully activates innate and adaptive immunity, significantly inhibiting CCA growth. Furthermore, as a combination therapy with anti-PD-1 immunotherapy, CM-TAC@Ce@PEG markedly enhances therapeutic efficacy and effectively prevents tumor recurrence. CONCLUSION: This work unveils an integrated strategy that integrating PDT with metabolic reprogramming and immune activation. Targeting SLC6A6-mediated redox dysregulation not only overcomes PDT resistance but also synergizes with immune checkpoint blockade, establishing a promising therapeutic strategy for CCA.