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Peer-reviewedCC BYACS nano

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

  • Amir Roshanzadeh1
  • Hyllana C D Medeiros1
  • Tessa Jordan1
  • Carson Malhado2
  • Katherine Espinoza Morelos3
  • Mohamed Khalil4,5
  • Jeyashri Muthukumar2
  • Laura Favazza6
  • Steven S Chang7,8
  • James M Hamby9
  • Laura C Cesa9
  • Dohun Pyeon4
3 more authors
  • Vincent Lavallo3
  • Richard R Lunt2,10
  • Sophia Y Lunt1,2
10 affiliations
  1. 1Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan48824, United States.
  2. 2Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, Michigan48824, United States.
  3. 3Department of Chemistry, University of California Riverside, Riverside, California92521, United States.
  4. 4Department of Microbiology, Genetics, and Immunology, Michigan State University, East Lansing, Michigan48824, United States.
  5. 5Department of Molecular Biology, National Research Center, Giza12622, Egypt.
  6. 6Department of Pathology and Laboratory Medicine, Henry Ford Health, Detroit, Michigan48202, United States.
  7. 7Department of Otolaryngology-Head and Neck Surgery, College of Human Medicine, Michigan State University, East Lansing, Michigan48824, United States.
  8. 8Department of Otolaryngology-Head and Neck Surgery, Henry Ford Health, Detroit, Michigan48202, United States.
  9. 9Entrepreneur-in-Residence (EIR) Spartan Innovations, Michigan State University, East Lansing, Michigan48824, United States.
  10. 10Department of Physics and Astronomy, Michigan State University, East Lansing, Michigan48824, United States.
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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.

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Cite

BibTeXRIS
BibTeX
@article{roshanzadeh2026cystinedependent,
  title = {{Cystine-Dependent Redox Metabolism Determines Photodynamic Therapy Response in Head and Neck Squamous Cell Carcinoma.}},
  author = {Amir Roshanzadeh and Hyllana C D Medeiros and Tessa Jordan and Carson Malhado and Katherine Espinoza Morelos and Mohamed Khalil and Jeyashri Muthukumar and Laura Favazza and Steven S Chang and James M Hamby and Laura C Cesa and Dohun Pyeon and Vincent Lavallo and Richard R Lunt and Sophia Y Lunt},
  journal = {ACS nano},
  year = {2026},
  month = sep,
  doi = {10.1021/acsnano.6c10240},
  url = {https://europepmc.org/article/MED/42916079},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Cystine-Dependent Redox Metabolism Determines Photodynamic Therapy Response in Head and Neck Squamous Cell Carcinoma.
AU  - Amir Roshanzadeh
AU  - Hyllana C D Medeiros
AU  - Tessa Jordan
AU  - Carson Malhado
AU  - Katherine Espinoza Morelos
AU  - Mohamed Khalil
AU  - Jeyashri Muthukumar
AU  - Laura Favazza
AU  - Steven S Chang
AU  - James M Hamby
AU  - Laura C Cesa
AU  - Dohun Pyeon
AU  - Vincent Lavallo
AU  - Richard R Lunt
AU  - Sophia Y Lunt
PY  - 2026
DA  - 2026/09/01
JO  - ACS nano
DO  - 10.1021/acsnano.6c10240
UR  - https://europepmc.org/article/MED/42916079
AB  - 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.
SN  - 1936-0851
SN  - 1936-086X
ER  -