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Updated: Sep 13, 2025

Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment
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Nrf2 Hyperactivation as a Driver of Radiotherapy Resistance and Suppressed Antitumor Immunity in Head and Neck

Rutulkumar Patel1,2, Kalil Saab1, Lixia Luo3

  • 1Department of Radiation Oncology, Baylor College of Medicine, Houston, Texas.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|July 31, 2025
PubMed
Abstract

Insights

Keap1 haploinsufficiency in head and neck squamous cell carcinoma (HNSCC) promotes radioresistance and aggressive growth. This NRF2 pathway activation creates an unfavorable tumor immune microenvironment, impacting treatment outcomes.

Area of Science:

  • Oncology
  • Cancer Biology
  • Radiation Oncology

Background:

  • Alterations in the KEAP1/NFE2L2 (NRF2)/CUL3 pathway are implicated in ~20% of head and neck squamous cell carcinomas (HNSCC).
  • These pathway alterations are associated with resistance to standard therapies.
  • The role of this pathway in HNSCC radioresistance remains understudied.

Purpose of the Study:

  • To investigate the role of the KEAP1/NRF2 pathway in radioresistance in HNSCC.
  • To examine the impact of Keap1 loss on the tumor immune microenvironment.
  • To understand the therapeutic implications of KEAP1/NRF2 pathway alterations in HNSCC.

Main Methods:

  • Generation of genetically engineered mouse models of HNSCC with Keap1 loss.
  • Development of primary murine cancer cell lines with common HNSCC mutations.
  • Analysis using Western blotting, immunohistochemistry, RNA sequencing (RNA-seq).
  • Fractionated radiation therapy applied to primary tumors.

Main Results:

  • Keap1 haploinsufficiency led to NRF2 pathway activation and a radioresistant phenotype in HNSCC cells.
  • RNA-seq revealed increased myeloid infiltration and enhanced angiogenic signatures in Keap1-haploinsufficient tumors.
  • Keap1 haploinsufficient HNSCC tumors exhibited significantly greater radioresistance and accelerated growth compared to controls.

Conclusions:

  • Keap1 haploinsufficiency in HNSCC is associated with an unfavorable tumor immune microenvironment.
  • This genetic alteration drives aggressive tumor growth and confers a radioresistant phenotype.
  • Targeting the KEAP1/NRF2 pathway may offer therapeutic strategies for radioresistant HNSCC.

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