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Updated: Jan 7, 2026

Isolation and Characterization of a Head and Neck Squamous Cell Carcinoma Subpopulation Having Stem Cell Characteristics
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Isolation and Characterization of a Head and Neck Squamous Cell Carcinoma Subpopulation Having Stem Cell Characteristics

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Cancer-Associated Fibroblasts-Derived Exosomes as Mediators of Immunotherapy Resistance in Head and Neck Squamous

Julia Federspiel1, Jozsef Dudas1, Benedikt Gabriel Hofauer1

  • 1Department of Otorhinolaryngology and Head and Neck Surgery, Medical University of Innsbruck, A-6020 Innsbruck, Austria.

Cells
|December 24, 2025
PubMed

Insights

Exosomes from head and neck squamous cell carcinoma (HNSCC) create an immunosuppressive tumor microenvironment (TME). These exosomes hinder immune checkpoint inhibitor (ICI) efficacy by suppressing T-cells and promoting immune escape.

Area of Science:

  • Oncology
  • Immunology
  • Cell Biology

Background:

  • The tumor microenvironment (TME) is critical for head and neck squamous cell carcinoma (HNSCC) progression and response to therapy.
  • Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have improved outcomes in advanced HNSCC.
  • Exosomes play a significant role in mediating intercellular communication within the TME.

Purpose of the Study:

  • To review recent publications on plasma-derived exosomes in HNSCC patients.
  • To summarize how tumor cell- and cancer-associated fibroblast-derived exosomes (CAF-Exos) modulate the TME and immune response.
  • To highlight the impact of exosomes on the efficacy of immunotherapies in HNSCC.

Main Methods:

  • Literature review of studies investigating exosomes in HNSCC.
  • Analysis of exosome content, including tumor and immune checkpoint markers.
  • Examination of exosome-mediated effects on immune cells (T-cells, B-cells, macrophages) and tumor cells.

Main Results:

  • Tumor cell-derived exosomes directly suppress cytotoxic T-lymphocytes.
  • CAF-Exos indirectly promote immune escape by excluding CD8+ T-cells, promoting regulatory T-cells (Tregs), and upregulating PD-L1.
  • Exosomes carry markers reflecting tumor burden and treatment response, and modulate immune cells to create an immunosuppressive niche.
  • Bidirectional miRNA transfer between tumor cells and CAFs via exosomes promotes epithelial-mesenchymal transition (EMT) and undermines ICI efficacy.

Conclusions:

  • Plasma-derived exosomes in HNSCC patients are valuable biomarkers for tumor burden and treatment response.
  • Exosomes, particularly CAF-Exos, significantly contribute to an immunosuppressive TME, hindering immunotherapy effectiveness.
  • Further functional and biomechanistic studies are needed to understand CAF subtype exosome roles in HNSCC immunoresistance.
Keywords:
EMTPD-L1 inhibitorscancer-associated fibroblastsexosomestumor microenvironment

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