ArticleClinical cancer research : an official journal of the American Association for Cancer Research2025
Nrf2 Hyperactivation as a Driver of Radiotherapy Resistance and Suppressed Antitumor Immunity in Head and Neck Squamous Cell Carcinoma.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Gut microbiota-derived metabolites as context-dependent modulators of Nrf2 signaling in inflammation-driven carcinogenesis.Gut microbes · 2026Review
- Article
- Targeting E3 ubiquitin ligases: Mechanistic breakthroughs and novel clinical translation pathways for tumor radioimmunotherapy.Molecular cancer · 2026Review
- Review
- Neddylation-dependent CUL3-KLHL12 E3 ligase drives microglial oxidative stress and neuroinflammation in traumatic brain injury by targeting GCLM for degradation.Journal of translational medicine · 2026Article
- Multidrug resistance in cancer: current understandings and future perspective.Molecular biomedicine · 2026Review
- Metabolism and Immunity-Adapted Radiotherapy (M.I.A.R): A Conceptual Framework for Overcoming the Therapeutic Plateau in Clinical Radiotherapy.Current oncology (Toronto, Ont.) · 2026Review
- An exosome-biomimetic photothermal nanocarrier for IGF2BP2 siRNA delivery and enhanced ferroptosis in head and neck squamous cell carcinoma.Materials today. Bio · 2026Article
- Advances in ferroptosis mechanisms and therapeutic potential in head and neck squamous cell carcinoma.Frontiers in cell and developmental biology · 2026Review
- From metabolism to genome integrity: NRF2 as a key mediator of cancer therapy response.Frontiers in cell and developmental biology · 2026Review
- Cold, Hot, and Lethal-The Tumour Microenvironment and the Immunology of Head and Neck Squamous Cell Carcinoma.International journal of molecular sciences · 2025Review
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Authors and funding
16 authors.
Funding
Abstract
purposeAlterations in the KEAP1/NFE2L2 (NRF2)/CUL3 pathway occur in ∼20% of human head and neck squamous cell carcinomas (HNSCC) and are associated with resistance to standard-of-care therapy. However, this pathway's role in radiotherapy resistance in HNSCC has not been well studied. EXPERIMENTAL
designWe generated genetically engineered mouse models and developed primary murine cancer cell lines harboring mutations commonly observed in human HNSCC, including inducible activation of PIK3CA and deletion of Trp53, with or without Keap1 loss. Primary tumors were initiated via 4-hydroxytamoxifen injection ± the tobacco carcinogen benzo[a]pyrene (BAP) into the oral buccal mucosa. Tumors were analyzed by Western blotting, IHC, and RNA sequencing and subjected to fractionated radiotherapy to investigate the role of the KEAP1/NRF2 pathway in radioresistance and modulation of the tumor-immune microenvironment.
resultsBAP exposure accelerated primary tumor formation within 1 month, with histologic analysis confirming invasive squamous cell carcinoma, validated by cytokeratin and differentiation marker expression. Primary cell lines derived from Keap1-haploinsufficient tumors exhibited upregulation of NRF2 target genes and a radioresistant phenotype, which was reversed after Nrf2 knockdown in vitro. Bulk RNA sequencing revealed that Keap1 haploinsufficiency correlated with NRF2 pathway activation, increased myeloid infiltration, and enhanced angiogenic signatures. In vivo, Keap1 haploinsufficiency promoted accelerated tumor growth and decreased survival. Finally, using fractionated radiotherapy, we showed that Keap1-haploinsufficient primary tumors were significantly more radioresistant than Keap1-proficient tumors, regardless of BAP exposure.
conclusionsThese data demonstrate that Keap1 haploinsufficiency in HNSCC is linked to unfavorable tumor-immune microenvironment, aggressive growth, and a radioresistant phenotype.
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