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Bridging the translational gap in HNSCC immunotherapy: From resistance mechanisms to high-fidelity preclinical models

Shasha Shen1, Juan Li1, Xue Cui1

  • 1Department of Head and Neck Oncology, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China.

Critical Reviews in Oncology/Hematology
|February 8, 2026
PubMed

Insights

Head and neck squamous cell carcinoma (HNSCC) shows limited response to immune checkpoint inhibitors (ICIs). High-fidelity models like patient-derived organoids are crucial for developing effective, biomarker-driven HNSCC therapies.

Area of Science:

  • Oncology
  • Immunotherapy
  • Translational Research

Background:

  • Head and neck squamous cell carcinoma (HNSCC) presents a significant therapeutic challenge, with immune checkpoint inhibitors (ICIs) offering benefit to only a subset of patients.
  • A critical translational gap exists between preclinical findings and clinical outcomes in HNSCC immunotherapy.

Purpose of the Study:

  • To analyze biological resistance mechanisms in HNSCC.
  • To evaluate the limitations of conventional preclinical models.
  • To advocate for advanced, high-fidelity models for improved HNSCC treatment strategies.

Main Methods:

  • Critical analysis of resistance drivers: immunosuppressive tumor microenvironment, TGF-β, hypoxia-driven metabolic checkpoints (adenosine signaling), and HPV status.
  • Evaluation of conventional models (2D cell lines, syngeneic mice, immunodeficient xenografts).
  • Proposal of high-fidelity platforms: Air-Liquid Interface (ALI) autologous patient-derived organoids (PDOs) and humanized mouse models.

Main Results:

  • Conventional models inadequately recapitulate human-specific resistance mechanisms and stromal complexities in HNSCC.
  • High-fidelity models like ALI PDOs and humanized mice offer superior recapitulation of HNSCC biology.
  • Integration into biomarker-driven co-clinical trials is proposed as essential for advancing HNSCC therapy.

Conclusions:

  • A paradigm shift towards high-fidelity preclinical models is necessary for HNSCC immunotherapy.
  • These advanced models facilitate precise patient stratification and rational trial design.
  • Standardization of high-fidelity protocols is key for clinical implementation in precision oncology for HNSCC.
Keywords:
Drug ResistanceHead Neck Squamous Cell CarcinomaHumanized MiceImmunotherapyOrganoidsPrecision MedicineTumor Microenvironment

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