{
  "abstract": "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan48824, United States.",
    "Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, Michigan48824, United States.",
    "Department of Chemistry, University of California Riverside, Riverside, California92521, United States.",
    "Department of Microbiology, Genetics, and Immunology, Michigan State University, East Lansing, Michigan48824, United States.",
    "Department of Molecular Biology, National Research Center, Giza12622, Egypt.",
    "Department of Pathology and Laboratory Medicine, Henry Ford Health, Detroit, Michigan48202, United States.",
    "Department of Otolaryngology-Head and Neck Surgery, College of Human Medicine, Michigan State University, East Lansing, Michigan48824, United States.",
    "Department of Otolaryngology-Head and Neck Surgery, Henry Ford Health, Detroit, Michigan48202, United States.",
    "Entrepreneur-in-Residence (EIR) Spartan Innovations, Michigan State University, East Lansing, Michigan48824, United States.",
    "Department of Physics and Astronomy, Michigan State University, East Lansing, Michigan48824, United States."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Amir Roshanzadeh"
    },
    {
      "affs": [
        0
      ],
      "name": "Hyllana C D Medeiros"
    },
    {
      "affs": [
        0
      ],
      "name": "Tessa Jordan"
    },
    {
      "affs": [
        1
      ],
      "name": "Carson Malhado"
    },
    {
      "affs": [
        2
      ],
      "name": "Katherine Espinoza Morelos"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Mohamed Khalil"
    },
    {
      "affs": [
        1
      ],
      "name": "Jeyashri Muthukumar"
    },
    {
      "affs": [
        5
      ],
      "name": "Laura Favazza"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "Steven S Chang"
    },
    {
      "affs": [
        8
      ],
      "name": "James M Hamby"
    },
    {
      "affs": [
        8
      ],
      "name": "Laura C Cesa"
    },
    {
      "affs": [
        3
      ],
      "name": "Dohun Pyeon"
    },
    {
      "affs": [
        2
      ],
      "name": "Vincent Lavallo",
      "orcid": "0000-0001-8945-3038"
    },
    {
      "affs": [
        1,
        9
      ],
      "name": "Richard R Lunt",
      "orcid": "0000-0003-4248-6312"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Sophia Y Lunt",
      "orcid": "0000-0003-4522-6065"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1eppepvmvzwnj.bib",
  "cited_by": 0,
  "doi": "10.1021/acsnano.6c10240",
  "fulltext_url": "https://europepmc.org/articles/PMC13602999",
  "id": "1eppepvmvzwnj",
  "issns": [
    "1936-0851",
    "1936-086X"
  ],
  "landing_url": "https://europepmc.org/article/MED/42916079",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2740|Photodynamic Therapy Research Studies"
    ]
  ],
  "openalex": "W7211911825",
  "pdf_url": "https://europepmc.org/articles/PMC13602999?pdf=render",
  "pmcid": "PMC13602999",
  "pmid": "42916079",
  "published": "2026-09-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/1eppepvmvzwnj.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:21:02Z",
      "native_id": "MED:42916079",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42916079"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2740|Photodynamic Therapy Research Studies",
      "subfield": "general"
    }
  ],
  "title": "Cystine-Dependent Redox Metabolism Determines Photodynamic Therapy Response in Head and Neck Squamous Cell Carcinoma.",
  "title_text": "Cystine-Dependent Redox Metabolism Determines Photodynamic Therapy Response in Head and Neck Squamous Cell Carcinoma.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:21:02Z",
  "url": "https://research.draconitic.com/paper/1eppepvmvzwnj",
  "venue": "ACS nano",
  "versions": []
}