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Cells
Special Issues
Emerging Mechanisms and Therapeutic Strategies in Head and Neck Cancer
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Emerging Mechanisms and Therapeutic Strategies in Head and Neck Cancer

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: 31 July 2026 | Viewed by 6687

Editors

Dr. Madalina Anca Moldovan

E-Mail Website
Guest Editor
Department of Oro-Maxillo-Facial Surgery and Implantology, Iuliu Hatieganu University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania
Interests: head and neck oncology; tumor microenvironment; tumor–stroma interaction; treatment resistance; radiotherapy sensitization; targeted therapy; precision oncology
Dr. Ciprian Tomuleasa

E-Mail Website
Guest Editor
1. Department of Haematology, Iuliu Hatieganu University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania
2. "Ion Chiricuță" Institute of Oncology, Cluj-Napoca, Romania
Interests: translational oncology; hematologic malignancies; stem cell biology; cancer stem cells; immunotherapy; cell-based therapies; tumor microenvironment; precision medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Head and neck cancer (HNC) includes varied tumors arising from the mucosal surfaces of the oral cavity, pharynx, and larynx, characterized by distinct molecular profiles and complex pathogenic pathways. Clinically, these malignancies are associated with significant morbidity and mortality, often requiring multimodal treatment approaches. While treatment advances have improved care, patients with advanced-stage disease or early-stage tumors demonstrating high-risk pathological features remain at elevated risk of poor outcomes due to persistent issues such as therapy resistance, locoregional relapse, and distant dissemination. A deeper understanding of the underlying cellular and molecular mechanisms that drive tumor progression, treatment response, and immune evasion is essential to improve patient outcomes and guide the development of more effective, personalized treatment strategies.

In recent years, significant progress has been made in elucidating the biological complexity of HNC, including the contributions of cancer stem cells, epithelial–mesenchymal transition, tumor–stroma interactions, immune modulation, and the oncogenic impact of viruses such as HPV. These findings are reshaping current perspectives on disease pathogenesis and revealing new opportunities for therapeutic innovation.

For this Special Issue, we invite original research articles and reviews that address emerging mechanisms and therapeutic strategies related to head and neck cancer. Areas of focus may include cellular signaling networks, resistance to conventional and targeted therapies, immunotherapeutic approaches, tumor microenvironment dynamics, biomarker development, and novel treatment combinations. We are particularly interested in studies that bridge basic science with translational and clinical relevance, contributing to advancing precision oncology in HNC.

Dr. Madalina Anca Moldovan
Dr. Ciprian Tomuleasa
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 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 microenvironment
  • epithelial–mesenchymal transition (EMT)
  • tumor–stroma interaction
  • treatment resistance
  • radiotherapy sensitization
  • targeted therapy
  • precision oncology

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Published Papers (5 papers)

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13 pages, 2072 KB  
Article
Radiosensitisation of Head and Neck Cancer Cells to Protons of Increasing LET Through Targeting DNA Double Strand Break Repair
by Elizabeth R. Dufficy, Amalia Goula, Emma Melia, Abigail Bellamy and Jason L. Parsons
Cells 2026, 15(10), 879; https://doi.org/10.3390/cells15100879 - 12 May 2026
Viewed by 574
Abstract
The use of proton beam therapy (PBT), as a more precision-targeted radiotherapy technique, is increasing in the treatment of head and neck squamous cell carcinoma (HNSCC). PBT benefits from the precise delivery of the radiation dose to the tumour via the Bragg peak. [...] Read more.
The use of proton beam therapy (PBT), as a more precision-targeted radiotherapy technique, is increasing in the treatment of head and neck squamous cell carcinoma (HNSCC). PBT benefits from the precise delivery of the radiation dose to the tumour via the Bragg peak. However, challenges still remain in the treatment of HNSCC with radiotherapy, particularly with tumour radioresistance and recurrence, requiring strategies leading to radiosensitisation. There are added complexities with the use of PBT given the increase in linear energy transfer (LET) at and around the Bragg peak, which can cause an altered cellular response compared to low-LET radiation. Nevertheless, targeting the cellular DNA damage response is considered an important strategy to enhance tumour cell killing caused by radiotherapy. Therefore, using specific inhibitors against the protein kinases ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related (ATR) and the DNA-dependent protein kinase catalytic subunit (DNA-Pkcs), we investigated their impact in radiosensitising HPV-negative HNSCC cells to PBT of increasing LET. We demonstrate that inhibitors against ATR (AZD6738), and particularly ATM (AZD1390) and DNA-Pkcs (AZD7648), could significantly decrease clonogenic survival of HNSCC cell lines following PBT at both low and relatively high LET (~2 keV/µm and ~8 keV/µm, respectively). We confirmed that the inhibitors in combination with PBT led to DSB persistence through neutral comet assays and monitoring γH2AX/53BP1 foci. We also show that this strategy can enhance the sensitivity of patient-derived organoids of HNSCC to PBT of both low and high LET, highlighting this as a strategy which should be exploited further. Full article
(This article belongs to the Special Issue Emerging Mechanisms and Therapeutic Strategies in Head and Neck Cancer)
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Review

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26 pages, 1441 KB  
Review
Ferroptosis in Differentiated Thyroid Cancer: Redox–Iodine Metabolism, Dedifferentiation, and Therapeutic Sensitization Beyond Anaplastic Disease
by Jaewang Lee and Jong-Lyel Roh
Cells 2026, 15(7), 630; https://doi.org/10.3390/cells15070630 - 31 Mar 2026
Viewed by 948
Abstract
Differentiated thyroid cancer (DTC), including papillary and follicular subtypes, is generally associated with favorable prognosis; however, a subset of patients develops recurrent, metastatic, or radioiodine-refractory diseases with limited therapeutic options. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has [...] Read more.
Differentiated thyroid cancer (DTC), including papillary and follicular subtypes, is generally associated with favorable prognosis; however, a subset of patients develops recurrent, metastatic, or radioiodine-refractory diseases with limited therapeutic options. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has recently emerged as a biologically relevant process in thyroid cancer, yet its role in differentiated disease remains incompletely defined. Unlike many other malignancies, thyroid cancer arises within an organ intrinsically shaped by iodine-dependent redox reactions required for thyroid hormone biosynthesis. This unique oxidative environment imposes selective pressure on tumor cells to adapt redox balance, lipid metabolism, and antioxidant defenses, all of which are central regulators of ferroptosis. Accumulating evidence indicates that ferroptosis susceptibility in DTC is dynamically modulated by differentiation status, oncogenic signaling, metabolic rewiring, and tumor microenvironmental interactions. Notably, progression toward radioiodine-refractory disease is accompanied by dedifferentiation and reinforcement of anti-ferroptotic programs, linking ferroptosis resistance to therapeutic failure. In this review, we synthesize recent original studies and contemporary reviews to provide a focused overview of ferroptosis in DTC, excluding anaplastic disease. We discuss thyroid-specific redox and iodine metabolism, genetic and metabolic determinants of ferroptosis sensitivity, lipid remodeling, and immune–microenvironmental interactions, and highlight translational opportunities for targeting ferroptosis in radioiodine-refractory DTC. By reframing ferroptosis as a context-dependent vulnerability rather than a universal death pathway, this review outlines a conceptual roadmap for integrating ferroptosis modulation into existing therapeutic strategies for DTC. Full article
(This article belongs to the Special Issue Emerging Mechanisms and Therapeutic Strategies in Head and Neck Cancer)
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36 pages, 4167 KB  
Review
Ancient and Emerging Nanostructures for Innovations to Fight Head and Neck Cancer
by Nina Kummer, Ömür Acet, Burcu Önal Acet, Mike Blueggel, Aya Khamis, Désirée Gül, Shirley K. Knauer and Roland H. Stauber
Cells 2026, 15(4), 339; https://doi.org/10.3390/cells15040339 - 13 Feb 2026
Cited by 1 | Viewed by 1285
Abstract
Head and neck squamous cell carcinoma (HNSCC) remains a major global health challenge due to its aggressive behavior, late-stage diagnosis, and high incidence of therapy resistance. At the cellular level, these clinical limitations are driven by profound alterations in oncogenic signaling, stress adaptation, [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) remains a major global health challenge due to its aggressive behavior, late-stage diagnosis, and high incidence of therapy resistance. At the cellular level, these clinical limitations are driven by profound alterations in oncogenic signaling, stress adaptation, DNA damage response pathways, and immune regulation within the tumor microenvironment. Advances in nanotechnology offer powerful opportunities to address these challenges by enabling targeted interference with cellular processes that govern tumor growth, survival, and therapy resistance. “Ancient” (i.e., established, long-studied) nanostructures, including mineral-based nanoparticles, natural biopolymers, and plant-derived nanovesicles, provide inherently biocompatible and bioactive platforms capable of modulating cellular signaling, redox balance, and immune responses. In parallel, emerging nanosystems—such as nanobodies, engineered exosomes, DNA origami, and stimuli-responsive smart nanoparticles—allow precise molecular targeting, controlled cargo release, and direct manipulation of intracellular pathways and intercellular communication. This manuscript synthesizes historical and contemporary developments in nanostructure design, highlighting how the integration of ancient materials with advanced nanotechnology can reshape therapeutic strategies for HNSCC. By targeting key cellular and microenvironmental processes, including DNA damage response signaling, redox homeostasis, immune regulation and stress-adaptive survival mechanisms, rather than drug delivery alone, these integrated nano-platforms offer promising avenues to overcome resistance mechanisms, reprogram the tumor microenvironment, and improve therapeutic precision and patient outcomes. Full article
(This article belongs to the Special Issue Emerging Mechanisms and Therapeutic Strategies in Head and Neck Cancer)
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22 pages, 2256 KB  
Review
Understanding the Tumor Microenvironment and Therapy Resistance in Head and Neck Squamous Cell Carcinoma
by Abhinav Bagchi and Ratna B. Ray
Cells 2026, 15(1), 44; https://doi.org/10.3390/cells15010044 - 25 Dec 2025
Cited by 1 | Viewed by 1634
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a group of cancers arising in the oropharyngeal and laryngeal regions. Lifestyle choices such as smoking, tobacco chewing, alcohol consumption, and human papillomavirus (HPV) infection are key risk factors. Therapeutic options include surgical resection, chemoradiotherapy, [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) is a group of cancers arising in the oropharyngeal and laryngeal regions. Lifestyle choices such as smoking, tobacco chewing, alcohol consumption, and human papillomavirus (HPV) infection are key risk factors. Therapeutic options include surgical resection, chemoradiotherapy, EGFR-targeting therapy, and immunotherapy. However, the treatments are limited by drug resistance, relapses, and poor response to immunotherapy, especially in advanced diseases. The difference in tissue types and HPV infection status may lead to significant variations in their tumor microenvironment (TME). The heterogeneity contributes to poor treatment response and the development of therapeutic resistance. Therefore, it is critical to have a deeper understanding of the complexities and heterogeneity in TME and its role in treatment resistance. In this review, we focused on tumor heterogeneity and the role of cancer and non-cancer cells in therapeutic resistance. We discussed the studies on human HNSCC, especially HPV-negative, and presented the diversity in the tumor microenvironment and treatment response. Furthermore, we address the existing and experimental therapeutics that target therapy resistance and may lead to a better understanding of the disease and improve therapeutic outcomes. Full article
(This article belongs to the Special Issue Emerging Mechanisms and Therapeutic Strategies in Head and Neck Cancer)
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18 pages, 751 KB  
Review
Cancer-Associated Fibroblasts-Derived Exosomes as Mediators of Immunotherapy Resistance in Head and Neck Squamous Cell Carcinoma
by Julia Federspiel, Jozsef Dudas, Benedikt Gabriel Hofauer, Barbara Wollenberg and Teresa Bernadette Steinbichler
Cells 2025, 14(24), 1978; https://doi.org/10.3390/cells14241978 - 12 Dec 2025
Cited by 5 | Viewed by 1347
Abstract
The tumor microenvironment (TME) orchestrates tumor growth, immune evasion, and therapeutic response in head and neck squamous cell carcinoma (HNSCC). Current immune checkpoint inhibitors (ICIs) target the programmed death receptor-1/programmed death-ligand 1 (PD-1/PD-L1) axis and improve survival in recurrent, metastatic, and locally advanced [...] Read more.
The tumor microenvironment (TME) orchestrates tumor growth, immune evasion, and therapeutic response in head and neck squamous cell carcinoma (HNSCC). Current immune checkpoint inhibitors (ICIs) target the programmed death receptor-1/programmed death-ligand 1 (PD-1/PD-L1) axis and improve survival in recurrent, metastatic, and locally advanced HNSCC. Tumor cells produced exosomes directly suppress cytotoxic T-lymphocytes activity by modulating immune checkpoint pathways and disrupting T-cell receptor signaling. Cancer-associated fibroblast-derived exosomes (CAF-Exos) function indirectly by conditioning immune escape and tumor growth. Together, these exosomal populations cooperate to create an immunosuppressive niche that hinders the efficacy of immunotherapies. CAF-Exos induce TME changes that exclude CD8+ T-cells, promote regulatory T-cells (Tregs), and upregulate PD-L1 expression in tumor cells. The bidirectional transfer of microRNAs (miRNAs) between tumor cells and CAFs enhances epithelial–mesenchymal transition (EMT), suppresses cytotoxic lymphocytes, and undermines ICI efficacy. This review article summarizes recent publications about plasma-derived exosomes from HNSCC patients. These exosomes carry tumor and immune checkpoint markers, reflect tumor burden and treatment response, and strongly modulate immune cells by suppressing T- and B-cell activity and promoting immunosuppressive macrophages. We encourage functional and biomechanistic future studies in the field of HNSCC that examine how CAF subtypes exosomes achieve an immunoresistant TME. Full article
(This article belongs to the Special Issue Emerging Mechanisms and Therapeutic Strategies in Head and Neck Cancer)
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