Cystine-Dependent Redox Metabolism Determines Photodynamic Therapy Response in Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinoma (HNSCC) remains difficult to treat without substantial functional and cosmetic morbidity, as current management relies largely on surgery, radiation, and chemotherapy. However, these approaches often fail to achieve effective tumor control in therapy-resistant HNSCC. Photodynamic therapy (PDT) has strong potential for HNSCC treatment because it enables spatially restricted tumor ablation while limiting damage to surrounding healthy tissue. Here, we apply a near-infrared (NIR) cyanine–carborate photosensitizer (PS) platform to HNSCC to identify a redox-based mechanism that limits PDT response in resistant cells and evaluate a strategy for sensitizing resistant cells. Using complementary human papillomavirus (HPV)-positive and -negative HNSCC models, we show that PDT induces acute oxidative stress and lipid peroxidation in both sensitive and resistant cells. However, resistant cells counter this stress through an adaptive redox response marked by increased xCT (SLC7A11)-dependent cystine utilization. This response sustains glutathione-linked antioxidant buffering, limits lipid peroxidation, and promotes survival under PDT. Genetic or pharmacologic disruption of cystine uptake prevents this adaptive defense, restores oxidative vulnerability, and sensitizes PDT-resistant HNSCC cells to treatment. Consistent with these mechanistic findings, cyanine–carborate-induced PDT with xCT (SLC7A11) inhibition markedly suppressed tumor growth in vivo. Together, these findings identify xCT-dependent cystine metabolism as a targetable vulnerability for therapeutic sensitization of resistant HNSCC to PDT.