{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T20:33:56Z","timestamp":1792096436804,"version":"4.4.0"},"reference-count":46,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Recurrent or metastatic head and neck squamous cell carcinoma (R\/M HNSCC) is an aggressive malignancy with a historically poor prognosis. Although immune checkpoint inhibitors (ICIs) targeting the PD-1\/PD-L1 axis have established a new first-line standard of care, durable clinical benefit is restricted to a minority of patients, while primary or acquired resistance remains a major clinical challenge. This narrative review aims to provide a conceptual clinical\u2013biological synthesis of immunotherapy in R\/M HNSCC through an anatomical and biomarker-driven lens, with a focus on characterizing potential shared features of \u201cexceptional responders\u201d. Methods: A targeted narrative literature search was conducted across PubMed\/MEDLINE and to identify key clinical trials and representative clinical reports of exceptional response to ICIs in R\/M HNSCC. The literature was not systematically synthesized to construct a conceptual clinical\u2013biological framework of response and resistance. Results: Landmark clinical data confirm durable survival benefits with frontline pembrolizumab-based regimens in selected PDL-1 positive populations compared to historical chemotherapy. Qualitative appraisal of illustrative cases and translational cohorts suggests a potential biological hypothesis: exceptional responders, defined as patients achieving unexpected, multi-year complete radiological, pathological, or metabolic remissions, often align with a favorable confluence of a pre-existing \u201chot\u201d or inflamed tumor microenvironment, preserved antigen presentation machinery, and elevated antigenic novelty driven by viral oncoproteins (HPV, EBV) or high mutational\/indel burdens. Conversely, primary and acquired resistance are conceptually associated with defects in antigen processing, immunosuppressive cellular barriers, and alternative immune checkpoints. Conclusions: Immunotherapy has fundamentally transformed R\/M HNSCC management, yet exceptional single-agent responses remain rare. Rather than a definitive or proven biological biomarker, the proposed blueprint represents an integrative hypothesis highlighting the complex interplay of baseline immune inflammation, genomic features, and viral drivers. Translating these observations into broader clinical benefit will require validated biomarker-driven personalization and rationally designed combination regimens.<\/jats:p>","DOI":"10.3390\/cancers18172790","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T16:47:13Z","timestamp":1787849233000},"page":"2790","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Deconstructing Exceptional Responses to Immune Checkpoint Inhibition in Recurrent or Metastatic Head and Neck Carcinoma: A Site-Specific Clinical\u2013Biological Synthesis"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4570-4899","authenticated-orcid":false,"given":"Giovanni","family":"Motta","sequence":"first","affiliation":[{"name":"Otolaryngology Head and Neck Surgery Unit, Azienda Ospedaliera di Rilievo Nazionale dei Colli, Ospedale Monaldi, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8762-3731","authenticated-orcid":false,"given":"Piero Giuseppe","family":"Meliante","sequence":"additional","affiliation":[{"name":"Otolaryngology Head and Neck Surgery Unit, Azienda Ospedaliera di Rilievo Nazionale dei Colli, Ospedale Monaldi, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale","family":"Capasso","sequence":"additional","affiliation":[{"name":"Otolaryngology Head and Neck Surgery Unit, Azienda Ospedaliera di Rilievo Nazionale dei Colli, Ospedale Monaldi, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5600-3938","authenticated-orcid":false,"given":"Francesco","family":"Chiari","sequence":"additional","affiliation":[{"name":"Otolaryngology, Head and Neck Unit, \u201cSanto Spirito\u201d Hospital, 65124 Pescara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Tortoriello","sequence":"additional","affiliation":[{"name":"Otolaryngology Head and Neck Surgery Unit, Azienda Ospedaliera di Rilievo Nazionale dei Colli, Ospedale Monaldi, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Cancer Genome Atlas Network (2015). Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature, 517, 576\u2013582.","DOI":"10.1038\/nature14129"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1056\/NEJMoa0802656","article-title":"Platinum-Based Chemotherapy plus Cetuximab in Head and Neck Cancer","volume":"359","author":"Vermorken","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3293","DOI":"10.1200\/JCO.2015.61.1509","article-title":"Immunology and Immunotherapy of Head and Neck Cancer","volume":"33","author":"Ferris","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1007\/s11912-020-00938-3","article-title":"The Immune Microenvironment in Head and Neck Squamous Cell Carcinoma: On Subsets and Subsites","volume":"22","author":"Wondergem","year":"2020","journal-title":"Curr. Oncol. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/164_2017_11","article-title":"Mechanisms of Resistance to Immune Checkpoint Antibodies","volume":"Volume 249","author":"Ramos","year":"2018","journal-title":"Handbook of Experimental Pharmacology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2","DOI":"10.6004\/jnccn.2025.0007","article-title":"NCCN Guidelines\u00ae Insights: Head and Neck Cancers, Version 2.2025","volume":"23","author":"Colevas","year":"2025","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.1056\/NEJMoa1602252","article-title":"Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck","volume":"375","author":"Ferris","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e194","DOI":"10.1093\/oncolo\/oyab036","article-title":"Long-term Outcomes with Nivolumab as First-line Treatment in Recurrent or Metastatic Head and Neck Cancer: Subgroup Analysis of CheckMate 141","volume":"27","author":"Gillison","year":"2022","journal-title":"Oncologist"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/S0140-6736(18)31999-8","article-title":"Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): A randomised, open-label, phase 3 study","volume":"393","author":"Cohen","year":"2019","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1016\/S0140-6736(19)32591-7","article-title":"Pembrolizumab Alone or with Chemotherapy versus Cetuximab with Chemotherapy for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (KEYNOTE-048): A Randomised, Open-Label, Phase 3 Study","volume":"394","author":"Burtness","year":"2019","journal-title":"Lancet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"115395","DOI":"10.1016\/j.ejca.2025.115395","article-title":"Pembrolizumab with or without chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma: 5-year follow-up from the randomized phase III KEYNOTE-048 study","volume":"221","author":"Tahara","year":"2025","journal-title":"Eur. J. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1177\/01455613221121237","article-title":"New Therapeutic Strategies in the Treatment of Stomal Recurrence After Total Laryngectomy: Role of Immunotherapy","volume":"104","author":"Mesolella","year":"2025","journal-title":"Ear Nose Throat J."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Meliante, P.G., Zoccali, F., de Vincentiis, M., Ralli, M., Petrella, C., Fiore, M., Minni, A., and Barbato, C. (2023). Diagnostic Predictors of Immunotherapy Response in Head and Neck Squamous Cell Carcinoma. Diagnostics, 13.","DOI":"10.3390\/diagnostics13050862"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"12189","DOI":"10.18632\/oncotarget.2608","article-title":"EBV-driven LMP1 and IFN-\u03b3 up-regulate PD-L1 in nasopharyngeal carcinoma: Implications for oncotargeted therapy","volume":"5","author":"Fang","year":"2014","journal-title":"Oncotarget"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1038\/s41591-021-01444-0","article-title":"Toripalimab or placebo plus chemotherapy as first-line treatment in advanced nasopharyngeal carcinoma: A multicenter randomized phase 3 trial","volume":"27","author":"Mai","year":"2021","journal-title":"Nat. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1038\/s43018-020-0096-5","article-title":"Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab","volume":"1","author":"Bratman","year":"2020","journal-title":"Nat. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"eaar3593","DOI":"10.1126\/science.aar3593","article-title":"Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy","volume":"362","author":"Cristescu","year":"2018","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e89829","DOI":"10.1172\/jci.insight.89829","article-title":"The head and neck cancer immune landscape and its immunotherapeutic implications","volume":"1","author":"Mandal","year":"2016","journal-title":"JCI Insight"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.ccell.2020.10.015","article-title":"Molecular Features of Cancers Exhibiting Exceptional Responses to Treatment","volume":"39","author":"Wheeler","year":"2021","journal-title":"Cancer Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.immuni.2019.11.014","article-title":"Immune Landscape of Viral- and Carcinogen-Driven Head and Neck Cancer","volume":"52","author":"Cillo","year":"2020","journal-title":"Immunity"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"678","DOI":"10.4049\/jimmunol.166.1.678","article-title":"Increased production of immature myeloid cells in cancer patients: A mechanism of immunosuppression in T cell response","volume":"166","author":"Almand","year":"2001","journal-title":"J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e000664","DOI":"10.1136\/jitc-2020-000664","article-title":"Bintrafusp alfa, a bifunctional fusion protein targeting TGF-\u03b2 and PD-L1, in advanced squamous cell carcinoma of the head and neck: Results from a phase I cohort","volume":"8","author":"Cho","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1186\/s13046-022-02481-4","article-title":"The immune microenvironment of HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma: A multiparametric quantitative and spatial analysis unveils a rationale to target treatment-na\u00efve tumors with immune checkpoint inhibitors","volume":"41","author":"Tosi","year":"2022","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1001\/jamaoncol.2018.4628","article-title":"Safety and Efficacy of Durvalumab with or Without Tremelimumab in Patients With PD-L1-Low\/Negative Recurrent or Metastatic HNSCC: The Phase 2 CONDOR Randomized Clinical Trial","volume":"5","author":"Siu","year":"2019","journal-title":"JAMA Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e98811","DOI":"10.1172\/jci.insight.98811","article-title":"Frameshift events predict anti-PD-1\/L1 response in head and neck cancer","volume":"3","author":"Hanna","year":"2018","journal-title":"JCI Insight"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1016\/S0140-6736(15)00055-0","article-title":"Nasopharyngeal Carcinoma","volume":"387","author":"Chua","year":"2016","journal-title":"Lancet"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1159\/000515441","article-title":"Spatial Intratumoral Heterogeneity Expression of PD-L1 Antigen in Head and Neck Squamous Cell Carcinoma","volume":"99","author":"Hirshoren","year":"2021","journal-title":"Oncology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1016\/S1470-2045(18)30495-9","article-title":"Camrelizumab (SHR-1210) Alone or in Combination with Gemcitabine Plus Cisplatin for Nasopharyngeal Carcinoma: Results from Two Single-Arm, Phase 1 Trials","volume":"19","author":"Fang","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1016\/S1470-2045(21)00302-8","article-title":"Camrelizumab Plus Gemcitabine and Cisplatin Versus Placebo Plus Gemcitabine and Cisplatin as First-Line Therapy for Recurrent or Metastatic Nasopharyngeal Carcinoma (CAPTAIN-1st): A Multicentre, Randomised, Double-Blind, Phase 3 Trial","volume":"22","author":"Yang","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1001\/jamaoncol.2020.2955","article-title":"Neoadjuvant Nivolumab or Nivolumab Plus Ipilimumab in Untreated Oral Cavity Squamous Cell Carcinoma: A Phase 2 Open-Label Randomized Clinical Trial","volume":"6","author":"Schoenfeld","year":"2020","journal-title":"JAMA Oncol."},{"key":"ref_32","first-page":"2665455","article-title":"Predictive and Prognostic Factors for Immunotherapy Response in Head and Neck Squamous Cell Carcinoma: A Narrative Review","volume":"19","author":"Sacco","year":"2026","journal-title":"Expert Rev. Clin. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1186\/s40425-019-0647-4","article-title":"Tumor mutational burden quantification from targeted gene panels: Major advancements and challenges","volume":"7","author":"Fancello","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1200\/JCO.2018.78.2276","article-title":"T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated with Pembrolizumab Across 20 Cancers: KEYNOTE-028","volume":"37","author":"Ott","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_35","first-page":"153","article-title":"Unraveling Resistance to Immune Checkpoint Inhibitors in HNSCC: From Mechanisms to Combination Therapies","volume":"8","author":"Zhao","year":"2025","journal-title":"Cancer Drug Resist."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e1151594","DOI":"10.1080\/2162402X.2016.1151594","article-title":"CTLA4 blockade reduces immature myeloid cells in head and neck squamous cell carcinoma","volume":"5","author":"Yu","year":"2016","journal-title":"OncoImmunology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3074","DOI":"10.1158\/1078-0432.CCR-18-1942","article-title":"Wnt\\beta-catenin pathway activation correlates with immune exclusion across human cancers","volume":"25","author":"Luke","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e143","DOI":"10.1016\/S1470-2045(17)30074-8","article-title":"iRECIST: Guidelines for response criteria for use in trials testing immunotherapeutics","volume":"18","author":"Seymour","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4355","DOI":"10.1016\/j.cell.2024.07.016","article-title":"LAG-3 and PD-1 Synergize on CD8+ T Cells to Drive T Cell Exhaustion and Hinder Autocrine IFN-\u03b3-Dependent Anti-Tumor Immunity","volume":"187","author":"Andrews","year":"2024","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Ghasemi, K. (2025). Tiragolumab and TIGIT: Pioneering the Next Era of Cancer Immunotherapy. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1568664"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Abraham, F.F., and Julian, R. (2025). Emerging and Investigational Systemic Therapies in Recurrent\/Metastatic Head and Neck Cancer After Progression on Immunotherapy. Cancers, 17.","DOI":"10.3390\/cancers17233817"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Zhao, H., Conconi, D., and Zhao, W. (2026). Antibody-Drug Conjugates in Recurrent or Metastatic HNSCC: Relevant Targets, Clinical Development, and Future Prospects. Front. Immunol., 17.","DOI":"10.3389\/fimmu.2026.1828131"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2533488","DOI":"10.1080\/2162402X.2025.2533488","article-title":"Immunogenic cell death and bystander killing: Expanding the therapeutic potential of modern antibody-drug conjugates","volume":"14","author":"Kepp","year":"2025","journal-title":"OncoImmunology"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Rossi, G., Tartaglia, F.C., Denaro, N., Ghidini, M., Goker, F., Garrone, O., Giann\u00ec, A.B., Del Fabbro, M., Tartaglia, G.M., and Bossi, P. (2026). Therapeutic vaccines targeting HPV epitopes in human papillomavirus\u2014Positive oropharyngeal cancer: A critical review. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1727804"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Perri, F., Ottaviano, M., Tomaciello, M., and De Felice, F. (2025). CAR-Based Cell Therapy in Head and Neck Cancer: A Comprehensive Review on Clinical Applicability. Cancers, 17.","DOI":"10.3390\/cancers17132215"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Hu, C., Liu, M., Li, Y., Zhao, Y., Sharma, A., Liu, H., and Schmidt-Wolf, I.G.H. (2023). Recent Advances and Future Perspectives of CAR-T Cell Therapy in Head and Neck Cancer. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1213716"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/17\/2790\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T04:50:19Z","timestamp":1788151819000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/17\/2790"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,27]]},"references-count":46,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["cancers18172790"],"URL":"https:\/\/doi.org\/10.3390\/cancers18172790","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,27]]}}}