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Decoding and Remodeling the Suppressive Tumor Immune Microenvironment in Head and Neck Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: 20 June 2026 | Viewed by 752

Special Issue Editors


E-Mail Website
Guest Editor
Departments of Head and Neck Surgery and Immunology, MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA
Interests: myeloid cells; tumor microenvironment; immunotherapy; biomaterials; radiation therapy; head and neck cancer

E-Mail Website
Guest Editor
Department of Head and Neck Surgery, MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA
Interests: spatial biology; tumor microenvironment; immuno-oncology; head and neck cancer

Special Issue Information

Dear Colleagues,

Tumorigenesis is not only mediated by tumor-intrinsic factors, but also by cell–cell interactions and signaling processes within the tumor immune microenvironment (TIME). The TIME comprises a diverse array of cellular components, including immune cells, cancer-associated fibroblasts (CAFs), neurons, and endothelial cells, in addition to non-cellular elements such as the extracellular matrix, growth factors, cytokines, and metabolites. The immune composition within the TIME can either suppress or promote tumor growth, thereby influencing disease progression and therapeutic response. Immunosuppressive populations such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs) play critical roles in dampening anti-tumor immunity. Growth factors such as vascular endothelial growth factor (VEGF) stimulate angiogenesis, facilitating tumor growth and metastasis. CAFs represent a major stromal component of the TIME, contributing to extracellular matrix remodeling and correlating with poor prognosis across multiple cancer types. Additionally, neurons engage in bidirectional interactions with tumor and immune cells to modulate immune function and promote tumorigenesis. Recent advances in single-cell and spatial technologies have enabled deeper functional and spatial characterization of these intricate interactions within the TIME. This Special Issue will highlight recent progress in the understanding of the TIME in head and neck cancer, with the goal of identifying novel therapeutic strategies and improving responses to current treatment regimens. Key topics will include the following: 

  1.  Application of single-cell and spatial technologies to characterize the TIME in head and neck tumors to elucidate mechanisms underlying therapeutic response and resistance.
  2. Definition of temporal dynamics of the TIME during treatment to uncover mechanisms driving host response.
  3. Identification and validation of novel immune and molecular biomarkers predictive of response to immunotherapy.
  4. Leverage of mechanistic insights into the TIME to inform rational design of clinical trials integrating combination immunotherapeutic strategies.
  5. Investigation of the role of immunosuppressive myeloid populations in tumor progression and evaluation of potential therapeutic approaches to remodel the TIME.

Dr. Andrew G. Sikora
Dr. Jennifer L. Anderson
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • tumor immune microenvironment (TIME)
  • cancer-mediated immunosuppression
  • myeloid cells
  • regulatory T cells
  • cytokines
  • anti-tumor immunity
  • immune modulation

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Published Papers (1 paper)

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Research

23 pages, 4124 KB  
Article
Tumor Implantation Site of Syngeneic Oral Cancer Models Differentially Induces Site-Dependent Local and Systemic Immunosuppression
by Andrea H. Molina, Gemalene M. Sunga, Shawn Nguyen, Neeraja Dharmaraj, Ratna Veeramachaneni, Roberto Rangel, Jeffrey N. Myers, Jeffrey D. Hartgerink, Andrew G. Sikora and Simon Young
Cancers 2026, 18(10), 1607; https://doi.org/10.3390/cancers18101607 - 15 May 2026
Viewed by 337
Abstract
Background/Objectives: Preclinical studies of head and neck squamous cell carcinoma (HNSCC) commonly use subcutaneous heterotopic (flank) tumor models for simplicity; however, orthotopic models may better reflect the native tumor environment. Direct comparisons of the tumor immune microenvironments (TIME) and tumor-draining lymph nodes (tdLNs) [...] Read more.
Background/Objectives: Preclinical studies of head and neck squamous cell carcinoma (HNSCC) commonly use subcutaneous heterotopic (flank) tumor models for simplicity; however, orthotopic models may better reflect the native tumor environment. Direct comparisons of the tumor immune microenvironments (TIME) and tumor-draining lymph nodes (tdLNs) between these models remain limited. Better understanding of site-specific immune differences could improve model selection and interpretation of translational HNSCC studies. Methods: ROC1 tumors were established in murine heterotopic and orthotopic sites, followed by assessment of tumor growth kinetics, survival, and the tumor microenvironment. Immune composition of tumors, blood, tdLNs, and spleen was evaluated at three tumor progression timepoints using multiparameter spectral flow cytometry. Results: Heterotopic and orthotopic tumor models showed similar growth kinetics and survival. Immune profiling revealed increased infiltration of CD3+ T-cells, natural killer (NK) cells, and myeloid populations in both models. Heterotopic tumors were enriched in dendritic cells (DCs), plasmacytoid DCs, and monocytic myeloid-derived suppressor cells (M-MDSCs), whereas orthotopic tumors showed increased macrophages, granulocytic MDSCs, and M-MDSCs. Despite temporal variation, both TIMEs were dominated by macrophages, DCs, and CD3+ T-cells. Late-stage heterotopic tumors contained more CD4+ T-cells. Reduced T-cell cytotoxicity (PD-1, CD107a) and increased immune checkpoint expression across myeloid cells indicated an immunosuppressive TIME. Systemically, effector cells were preserved despite suppressive cell trafficking, and tdLNs in both models exhibited immunosuppressive PD-L1 expression. Conclusions: Heterotopic and orthotopic ROC1 tumors share key immune features, but site-specific differences in the TIME and tdLNs reveal tissue-dependent regulation. These local effects align with systemic changes, supporting global tumor-associated immunosuppression. Full article
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