Abstract

Photodynamic Therapy (PDT) is a clinically established, non-invasive treatment for various cancers, relying on the generation of cytotoxic reactive oxygen species (ROS) from a photosensitizer, light, and molecular oxygen. A major limitation to PDT efficacy is the rapid consumption of oxygen during treatment, leading to localized tumor hypoxia. This induced hypoxic state not only curtails further ROS production but also activates pro-survival signaling pathways in cancer cells, contributing to treatment resistance and recurrence. This study investigates the **modification of hypoxic states** through targeted interventions at the cellular and membrane level to potentiate PDT. Specifically, we explore the use of membrane-targeting agents that influence mitochondrial respiration and oxygen diffusion across the cell membrane, thereby regulating the intracellular oxygen tension. Our findings demonstrate that pre-treatment with a novel membrane-active compound significantly delays the onset of PDT-induced hypoxia, leading to a sustained increase in singlet oxygen yield and a corresponding enhancement in apoptotic and necrotic cell death. These results highlight a critical role for membrane-mediated oxygen dynamics in overcoming PDT resistance and provide a promising strategy for improving the clinical outcome of photodynamic cancer treatment.