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HPV-positive tumours generally tend to have a better prognosis and are driven by oncoproteins E6 and E7. In contrast, HPV-negative tumours typically have a worse prognosis and are often linked to mutations in tumour suppressor genes. HNSCCs exist within a complex environment known as the tumour microenvironment (TME). The TME includes tumour cells, cancer stem cells (CSCs), cancer-associated fibroblasts (CAFs), immune cells, extracellular matrix (ECM), blood vessels, and various signalling molecules. These components support tumour progression, invasion, metastasis, and resistance to treatment. Intercellular signalling within the TME\u2014mediated by cytokines such as IL-6, TGF-b, and galectins\u2014further promotes tumour growth and systemic effects like cachexia. Notably, the TME shares features with granulation tissue during wound healing, supporting the concept of cancer as a chronic, non-resolving wound. Effective therapy must target not only tumour cells but also the dynamic TME.<\/jats:p>","DOI":"10.3390\/ijms26188844","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T10:50:04Z","timestamp":1757587804000},"page":"8844","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Cold, Hot, and Lethal\u2014The Tumour Microenvironment and the Immunology of Head and Neck Squamous Cell Carcinoma"],"prefix":"10.3390","volume":"26","author":[{"given":"Svatava","family":"Vyhn\u00e1nkov\u00e1","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology 3FM CU and UHKV, Charles University, 10034 Prague, Czech Republic"},{"name":"Institute of Anatomy of the 1st Faculty of Medicine, Charles University, 12800 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1750-9933","authenticated-orcid":false,"given":"Luk\u00e1\u0161","family":"Lacina","sequence":"additional","affiliation":[{"name":"Institute of Anatomy of the 1st Faculty of Medicine, Charles University, 12800 Prague, Czech Republic"},{"name":"General University Hospital, 12800 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9087-0269","authenticated-orcid":false,"given":"Martin","family":"Chovanec","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology 3FM CU and UHKV, Charles University, 10034 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Plz\u00e1k","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery First Faculty of Medicine Charles University and University Hospital Motol, 15000 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7878-8403","authenticated-orcid":false,"suffix":"Jr.","given":"Karel","family":"Smetana","sequence":"additional","affiliation":[{"name":"Institute of Anatomy of the 1st Faculty of Medicine, Charles University, 12800 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8268-4999","authenticated-orcid":false,"given":"Ji\u0159\u00ed","family":"Netu\u0161il","sequence":"additional","affiliation":[{"name":"Institute of Molecular Genetics of the Czech Academy of Sciences, 14200 Prague, Czech Republic"},{"name":"Faculty of Science, Charles University, 12800 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4593-1525","authenticated-orcid":false,"given":"Michal","family":"Kol\u00e1\u0159","sequence":"additional","affiliation":[{"name":"Institute of Molecular Genetics of the Czech Academy of Sciences, 14200 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8188-6971","authenticated-orcid":false,"given":"Radek","family":"\u0160indelka","sequence":"additional","affiliation":[{"name":"Laboratory of Gene Expression, Institute of Biotechnology of the Czech Academy of Sciences, 25250 Vestec, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"66226","DOI":"10.18632\/oncotarget.11265","article-title":"The Etiologic Spectrum of Head and Neck Squamous Cell Carcinoma in Young Patients","volume":"7","author":"Liu","year":"2016","journal-title":"Oncotarget"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Barsouk, A., Aluru, J.S., Rawla, P., Saginala, K., and Barsouk, A. 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