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Updated: Mar 7, 2026

Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment
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Tumor microenvironment-driven immune evasion and therapeutic strategies in head and neck squamous cell carcinoma

Ingeborg Tinhofer1, Anne-Sophie Fisch

  • 1Department of Radiooncology and Radiotherapy, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Current Opinion in Oncology
|March 6, 2026
PubMed
Abstract

Insights

Head and neck squamous cell carcinoma (HNSCC) tumor microenvironments (TME) resist immune checkpoint inhibitors (ICIs). Targeting TME barriers with novel combinations shows promise for improving durable responses in HNSCC patients.

Area of Science:

  • Oncology
  • Immunology
  • Cancer Biology

Background:

  • Head and neck squamous cell carcinoma (HNSCC) exhibits a complex tumor microenvironment (TME) that promotes immune evasion.
  • Immune checkpoint inhibitors (ICIs) have limited durable response rates in HNSCC due to stromal barriers, myeloid cell infiltration, and metabolic constraints within the TME.

Purpose of the Study:

  • To review the mechanisms of immune resistance within the HNSCC TME.
  • To highlight emerging therapeutic strategies targeting the TME to enhance ICI efficacy.

Main Methods:

  • Utilizing multiplex immunohistochemistry/immunofluorescence (IHC/mIF).
  • Employing single-cell and spatial omics technologies.
  • Conducting computational TME profiling.

Main Results:

  • Identified resistance mechanisms including CAF-driven immune exclusion, myeloid cell recruitment via chemokines and hypoxia, and nutrient/oxygen competition impacting effector T cells.
  • Highlighted TME-targeted combinations with PD-(L)1 blockade, such as VEGFR/multikinase inhibitors, TGF-β/CAF-directed agents, myeloid/chemokine modulators, and metabolic interventions.

Conclusions:

  • The HNSCC TME presents both a significant barrier and a therapeutic target.
  • Integrating high-resolution TME profiling into clinical trials is essential for selecting optimal TME-matched combinations and identifying patient subsets likely to benefit from immunotherapy.
Keywords:
cancer-associated fibroblastshead and neck squamous cell carcinomaimmune checkpoint inhibitionspatial omicstumor microenvironment

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