{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T18:05:48Z","timestamp":1780596348540,"version":"3.54.1"},"reference-count":87,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"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: Perioperative immunotherapy has emerged as a promising strategy for improving outcomes in patients with resectable head and neck squamous cell carcinoma (HNSCC). However, its biological rationale, clinical evidence, and optimal implementation remain incompletely defined. Methods: We conducted a narrative review of the current literature, integrating preclinical and clinical evidence on perioperative immune checkpoint inhibitor (ICI) therapy in resectable HNSCC, with particular attention to the immunological impact of surgery, tumor-draining lymph nodes, and treatment sequencing. Results: Neoadjuvant immunotherapy exploits the presence of intact tumor antigen and preserved lymphatic architecture, enabling broad T-cell priming, clonal expansion, and systemic immune memory formation. In contrast, adjuvant immunotherapy primarily targets residual microscopic disease and relies on preexisting tumor-reactive T cells, suggesting that these strategies are biologically distinct. Early-phase clinical trials have demonstrated the safety and feasibility of perioperative ICIs, with evidence of pathological responses. Recent phase III trials, including KEYNOTE-689 and NIVOPOSTOP, have provided practice-relevant evidence supporting the integration of ICIs into perioperative treatment, demonstrating improved event-free survival and clinical outcomes in selected populations. Several challenges remain, including optimal patient selection, lack of validated biomarkers, and treatment sequencing after perioperative ICI exposure. Conclusions: Perioperative immunotherapy represents a promising practice-relevant strategy in resectable HNSCC. Further studies are required to refine patient selection, develop predictive biomarkers, and optimize treatment sequencing to maximize clinical benefit.<\/jats:p>","DOI":"10.3390\/cancers18111845","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T17:11:04Z","timestamp":1780593064000},"page":"1845","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Basic and Clinical Evidence for Perioperative Immunotherapy in Resectable HNSCC"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-1348-3331","authenticated-orcid":false,"given":"Shota","family":"Sakaue","sequence":"first","affiliation":[{"name":"Department of Otolaryngology Head & Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa 078-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8506-928X","authenticated-orcid":false,"given":"Michihisa","family":"Kono","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head & Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa 078-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3411-671X","authenticated-orcid":false,"given":"Takumi","family":"Kumai","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head & Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa 078-8510, Japan"},{"name":"Department of Innovative Head & Neck Cancer Research and Treatment, Asahikawa Medical University, Asahikawa 078-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2457-9063","authenticated-orcid":false,"given":"Takahiro","family":"Inoue","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head & Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa 078-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4826-9829","authenticated-orcid":false,"given":"Hisataka","family":"Ominato","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head & Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa 078-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miki","family":"Takahara","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head & Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa 078-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Barsouk, A., Aluru, J.S., Rawla, P., Saginala, K., and Barsouk, A. (2023). Epidemiology, Risk Factors, and Prevention of Head and Neck Squamous Cell Carcinoma. Med. Sci., 11.","DOI":"10.3390\/medsci11020042"},{"key":"ref_2","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","first-page":"7","article-title":"Cancer statistics, 2022","volume":"72","author":"Siegel","year":"2022","journal-title":"CA Cancer J. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s41572-023-00418-5","article-title":"Author Correction: Head and neck squamous cell carcinoma","volume":"9","author":"Johnson","year":"2023","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.1016\/j.annonc.2020.07.011","article-title":"Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"31","author":"Machiels","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1056\/NEJMoa032641","article-title":"Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer","volume":"350","author":"Bernier","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.1056\/NEJMoa032646","article-title":"Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck","volume":"350","author":"Cooper","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.radonc.2009.04.014","article-title":"Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients","volume":"92","author":"Pignon","year":"2009","journal-title":"Radiother. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1200\/JCO.2003.01.008","article-title":"An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer","volume":"21","author":"Adelstein","year":"2003","journal-title":"J. Clin. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1002\/hed.20279","article-title":"Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501)","volume":"27","author":"Bernier","year":"2005","journal-title":"Head. Neck"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/S0140-6736(00)90011-4","article-title":"Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: Three meta-analyses of updated individual data","volume":"355","author":"Pignon","year":"2000","journal-title":"Lancet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1158\/2159-8290.CD-18-0367","article-title":"Fundamental Mechanisms of Immune Checkpoint Blockade Therapy","volume":"8","author":"Wei","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1126\/science.aaa8172","article-title":"The future of immune checkpoint therapy","volume":"348","author":"Sharma","year":"2015","journal-title":"Science"},{"key":"ref_14","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 squamous cell carcinoma of the head and neck (KEYNOTE-048): A randomised, open-label, phase 3 study","volume":"394","author":"Burtness","year":"2019","journal-title":"Lancet"},{"key":"ref_15","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_16","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1200\/JCO.21.02508","article-title":"Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study","volume":"41","author":"Harrington","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1056\/NEJMoa2312695","article-title":"Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma","volume":"390","author":"Choueiri","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1056\/NEJMoa2409932","article-title":"Overall Survival with Pembrolizumab in Early-Stage Triple-Negative Breast Cancer","volume":"391","author":"Schmid","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1016\/S0140-6736(24)01808-7","article-title":"Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11\/GOG-3047\/KEYNOTE-A18): Overall survival results from a randomised, double-blind, placebo-controlled, phase 3 trial","volume":"404","author":"Lorusso","year":"2024","journal-title":"Lancet"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1056\/NEJMoa2302983","article-title":"Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer","volume":"389","author":"Wakelee","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1056\/NEJMoa1802357","article-title":"Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma","volume":"378","author":"Eggermont","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1056\/NEJMoa2415434","article-title":"Neoadjuvant and Adjuvant Pembrolizumab in Locally Advanced Head and Neck Cancer","volume":"393","author":"Uppaluri","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/S0140-6736(25)01850-1","article-title":"Nivolumab added to cisplatin and radiotherapy versus cisplatin and radiotherapy alone after surgery for people with squamous cell carcinoma of the head and neck at a high risk of relapse (GORTEC 2018-01 NIVOPOST-OP): A randomised, open-label, phase 3 trial","volume":"407","author":"Bourhis","year":"2026","journal-title":"Lancet"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/S1470-2045(20)30737-3","article-title":"Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: A randomised, double-blind, placebo-controlled, multicentre, phase 3 trial","volume":"22","author":"Lee","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/S1470-2045(24)00100-1","article-title":"Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (KEYNOTE-412): A randomised, double-blind, phase 3 trial","volume":"25","author":"Machiels","year":"2024","journal-title":"Lancet Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s12663-019-01239-4","article-title":"Incidence of Micrometastasis and Isolated Tumour Cells in Clinicopathologically Node-Negative Head and Neck Squamous Cell Carcinoma","volume":"19","author":"Majumdar","year":"2020","journal-title":"J. Maxillofac. Oral. Surg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.surge.2010.07.011","article-title":"Surgery induced immunosuppression","volume":"9","author":"Hogan","year":"2011","journal-title":"Surgeon"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1067\/msy.2000.103498","article-title":"Suppression of cellular immunity by surgical stress","volume":"127","author":"Ogawa","year":"2000","journal-title":"Surgery"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1002\/bjs.1800721002","article-title":"The influence of surgical operations on components of the human immune system","volume":"72","author":"Lennard","year":"1985","journal-title":"Br. J. Surg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.3945\/ajcn.2010.29532","article-title":"Perioperative arginine-supplemented nutrition in malnourished patients with head and neck cancer improves long-term survival","volume":"92","author":"Buijs","year":"2010","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"106795","DOI":"10.1016\/j.oraloncology.2024.106795","article-title":"Enhanced oral versus flank lymph node T cell response parallels anti-PD1 efficacy in head and neck cancer","volume":"152","author":"Kono","year":"2024","journal-title":"Oral. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"eaax0182","DOI":"10.1126\/science.aax0182","article-title":"Neoadjuvant checkpoint blockade for cancer immunotherapy","volume":"367","author":"Topalian","year":"2020","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e008026","DOI":"10.1136\/jitc-2023-008026","article-title":"Tumor-draining lymph nodes: Opportunities, challenges, and future directions in colorectal cancer immunotherapy","volume":"12","author":"Wang","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4049","DOI":"10.1016\/j.cell.2022.09.020","article-title":"The primordial differentiation of tumor-specific memory CD8(+) T cells as bona fide responders to PD-1\/PD-L1 blockade in draining lymph nodes","volume":"185","author":"Huang","year":"2022","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4298","DOI":"10.1038\/s41467-022-31941-w","article-title":"Lymphatic-preserving treatment sequencing with immune checkpoint inhibition unleashes cDC1-dependent antitumor immunity in HNSCC","volume":"13","author":"Faraji","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5140","DOI":"10.1158\/1078-0432.CCR-20-1695","article-title":"Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus-Unrelated Head and Neck Cancer: A Multicenter, Phase II Trial","volume":"26","author":"Uppaluri","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.immuni.2013.07.012","article-title":"Oncology meets immunology: The cancer-immunity cycle","volume":"39","author":"Chen","year":"2013","journal-title":"Immunity"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/nature21349","article-title":"Elements of cancer immunity and the cancer-immune set point","volume":"541","author":"Chen","year":"2017","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/nature13988","article-title":"Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens","volume":"515","author":"Gubin","year":"2014","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/nrc3239","article-title":"The blockade of immune checkpoints in cancer immunotherapy","volume":"12","author":"Pardoll","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1146\/annurev-immunol-042617-053402","article-title":"Cancer Neoantigens","volume":"37","author":"Schumacher","year":"2019","journal-title":"Annu. Rev. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1126\/science.aaa4971","article-title":"Neoantigens in cancer immunotherapy","volume":"348","author":"Schumacher","year":"2015","journal-title":"Science"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5743","DOI":"10.1158\/1078-0432.CCR-18-2641","article-title":"The Promise of Neoadjuvant Immunotherapy and Surgery for Cancer Treatment","volume":"25","author":"Hoefsmit","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1158\/1078-0432.CCR-19-2209","article-title":"Neoadjuvant PD-1 Immune Checkpoint Blockade Reverses Functional Immunodominance among Tumor Antigen-Specific T Cells","volume":"26","author":"Friedman","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s00106-025-01683-4","article-title":"Neoadjuvant concepts compared to adjuvant and perioperative strategies in the treatment of head and neck cancer","volume":"74","author":"Schmidl","year":"2026","journal-title":"HNO"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/cr.2016.149","article-title":"Innate immune signaling and regulation in cancer immunotherapy","volume":"27","author":"Corrales","year":"2017","journal-title":"Cell Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/nature14404","article-title":"Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity","volume":"523","author":"Spranger","year":"2015","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"eaal1713","DOI":"10.1126\/sciimmunol.aal1713","article-title":"Intratumoral delivery of inactivated modified vaccinia virus Ankara (iMVA) induces systemic antitumor immunity via STING and Batf3-dependent dendritic cells","volume":"2","author":"Dai","year":"2017","journal-title":"Sci. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"114141","DOI":"10.1016\/j.celrep.2024.114141","article-title":"Batf3(+) DCs and the 4-1BB\/4-1BBL axis are required at the effector phase in the tumor microenvironment for PD-1\/PD-L1 blockade efficacy","volume":"43","author":"Ziblat","year":"2024","journal-title":"Cell Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1016\/j.immuni.2018.09.024","article-title":"Successful Anti-PD-1 Cancer Immunotherapy Requires T Cell-Dendritic Cell Crosstalk Involving the Cytokines IFN-gamma and IL-12","volume":"49","author":"Garris","year":"2018","journal-title":"Immunity"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1158\/2159-8290.CD-15-0510","article-title":"Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells","volume":"6","author":"Cueto","year":"2016","journal-title":"Cancer Discov."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1093\/jnci\/djaa216","article-title":"Neoadjuvant Immunotherapy for High-Risk, Resectable Malignancies: Scientific Rationale and Clinical Challenges","volume":"113","author":"Krishnamoorthy","year":"2021","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1097\/CCO.0000000000000940","article-title":"Window-of-opportunity clinical trials for biomarker discovery in head and neck squamous cell carcinoma","volume":"35","author":"Marret","year":"2023","journal-title":"Curr. Opin. Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1001\/jamaoto.2025.0410","article-title":"Neoadjuvant Therapy for Mucosal Head and Neck Squamous Cell Carcinoma: A Review From the American Head and Neck Society","volume":"151","author":"Contrera","year":"2025","journal-title":"JAMA Otolaryngol. Head. Neck Surg."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1111\/cas.14816","article-title":"CD4(+) and CD8(+) T cells in sentinel nodes exhibit distinct pattern of PD-1, CD69, and HLA-DR expression compared to tumor tissue in oral squamous cell carcinoma","volume":"112","author":"Piersiala","year":"2021","journal-title":"Cancer Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.21873\/anticanres.18010","article-title":"Neck Dissection and Immune Checkpoint Inhibitor Efficacy in Head and Neck Cancer: A Retrospective Study","volume":"46","author":"Iwasa","year":"2026","journal-title":"Anticancer Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1038\/s41591-019-0522-3","article-title":"Clonal replacement of tumor-specific T cells following PD-1 blockade","volume":"25","author":"Yost","year":"2019","journal-title":"Nat. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1158\/1078-0432.CCR-21-3351","article-title":"Phase II Clinical Trial of Neoadjuvant and Adjuvant Pembrolizumab in Resectable Local-Regionally Advanced Head and Neck Squamous Cell Carcinoma","volume":"28","author":"Gulati","year":"2022","journal-title":"Clin. Cancer Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e002568","DOI":"10.1136\/jitc-2021-002568","article-title":"Neoadjuvant nivolumab for patients with resectable HPV-positive and HPV-negative squamous cell carcinomas of the head and neck in the CheckMate 358 trial","volume":"9","author":"Ferris","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"7348","DOI":"10.1038\/s41467-021-26472-9","article-title":"Neoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma","volume":"12","author":"Vos","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1001\/jamaoto.2022.2291","article-title":"Association of Neoadjuvant Pembrolizumab for Oral Cavity Squamous Cell Carcinoma with Adverse Events After Surgery in Treatment-Naive Patients","volume":"148","author":"Tang","year":"2022","journal-title":"JAMA Otolaryngol. Head. Neck Surg."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1001\/jamaoto.2021.2191","article-title":"Neoadjuvant PD-1\/PD-L1 Inhibitors for Resectable Head and Neck Cancer: A Systematic Review and Meta-analysis","volume":"147","author":"Masarwy","year":"2021","journal-title":"JAMA Otolaryngol. Head. Neck Surg."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1001\/jamaoto.2025.4573","article-title":"Pathologic Response and Survival After Neoadjuvant Immunotherapy for Resectable Mucosal HNSCC: A Systematic Review and Meta-Analysis","volume":"152","author":"Mastrolonardo","year":"2026","journal-title":"JAMA Otolaryngol. Head. Neck Surg."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1001\/jamaoto.2025.1707","article-title":"Pathologic Treatment Effect and Survival in HPV-Negative HNSCC Following Neoadjuvant Nivolumab","volume":"151","author":"Moroco","year":"2025","journal-title":"JAMA Otolaryngol. Head. Neck Surg."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1158\/1078-0432.CCR-23-3249","article-title":"A Phase II Open-Label Randomized Clinical Trial of Preoperative Durvalumab or Durvalumab plus Tremelimumab in Resectable Head and Neck Squamous Cell Carcinoma","volume":"30","author":"Kim","year":"2024","journal-title":"Clin. Cancer Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1007\/s10147-020-01666-1","article-title":"Rationale of combination of anti-PD-1\/PD-L1 antibody therapy and radiotherapy for cancer treatment","volume":"25","author":"Sato","year":"2020","journal-title":"Int. J. Clin. Oncol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/nri.2016.107","article-title":"Immunogenic cell death in cancer and infectious disease","volume":"17","author":"Galluzzi","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e002485","DOI":"10.1136\/jitc-2021-002485","article-title":"Neoadjuvant immunoradiotherapy results in high rate of complete pathological response and clinical to pathological downstaging in locally advanced head and neck squamous cell carcinoma","volume":"9","author":"Leidner","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Wang, K., Gui, L., Lu, H., He, X., Li, D., Liu, C., Liu, S., and Wang, X. (2023). Efficacy and safety of pembrolizumab with preoperative neoadjuvant chemotherapy in patients with resectable locally advanced head and neck squamous cell carcinomas. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1189752"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"5206","DOI":"10.1245\/s10434-025-17195-y","article-title":"Neoadjuvant Chemoimmunotherapy for Resectable Head and Neck Squamous Cell Carcinoma: Systematic Review and Meta-analysis","volume":"32","author":"Cao","year":"2025","journal-title":"Ann. Surg. Oncol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1038\/s41467-024-46444-z","article-title":"Neoadjuvant chemo-immunotherapy with camrelizumab plus nab-paclitaxel and cisplatin in resectable locally advanced squamous cell carcinoma of the head and neck: A pilot phase II trial","volume":"15","author":"Wu","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Feng, Y., Qiao, W., Li, Z., and Li, Y. (2025). Comparative efficacy and safety of neoadjuvant immunotherapy vs chemotherapy in resectable head and neck squamous cell carcinoma: An umbrella review of randomized controlled trials and single-arm studies. BMC Med., 23.","DOI":"10.1186\/s12916-025-04441-z"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Gao, W., Feng, L., Zhao, X., Huang, Z., Chen, D., Yin, G., Guo, W., Zhong, Q., Chen, X., and Fang, J. (2024). Comparison of the efficacy and safety of neoadjuvant PD-1 inhibitors plus chemotherapy vs targeted therapy plus chemotherapy in locally advanced hypopharyngeal squamous cell carcinoma. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1466310"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Liu, C., Li, M., Liu, X., Shi, T., Wang, Y., Sui, C., Zhang, W., and Wang, B. (2024). Evaluating the efficacy and safety of different neoadjuvant immunotherapy combinations in locally advanced HNSCC: A systematic review and meta-analysis. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1467306"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2713","DOI":"10.1245\/s10434-024-16587-w","article-title":"Neoadjuvant Immunotherapy in Resectable HNSCC: An Updated Systematic Review and Meta-analysis","volume":"32","author":"Widjaja","year":"2025","journal-title":"Ann. Surg. Oncol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"107598","DOI":"10.1016\/j.phrs.2025.107598","article-title":"Neoadjuvant chemoimmunotherapy for locally advanced squamous cell carcinoma of the head and neck: Systematic review and meta-analysis","volume":"212","author":"Zhu","year":"2025","journal-title":"Pharmacol. Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"103018","DOI":"10.1016\/j.ctrv.2025.103018","article-title":"Comparative review of KEYNOTE-689 and NIVOPOSTOP trials and their impact on perioperative immunotherapy in locally advanced head and neck cancer","volume":"140","author":"Imamura","year":"2025","journal-title":"Cancer Treat. Rev."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1001\/jama.2025.1483","article-title":"Atezolizumab in High-Risk Locally Advanced Squamous Cell Carcinoma of the Head and Neck: A Randomized Clinical Trial","volume":"333","author":"Haddad","year":"2025","journal-title":"JAMA"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3464","DOI":"10.1158\/1078-0432.CCR-21-4554","article-title":"Phase II Trial of Adjuvant Nivolumab Following Salvage Resection in Patients with Recurrent Squamous Cell Carcinoma of the Head and Neck","volume":"28","author":"Leddon","year":"2022","journal-title":"Clin. Cancer Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"4960","DOI":"10.1158\/1078-0432.CCR-17-2386","article-title":"Baseline Tumor Size Is an Independent Prognostic Factor for Overall Survival in Patients with Melanoma Treated with Pembrolizumab","volume":"24","author":"Joseph","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"107954","DOI":"10.1016\/j.oraloncology.2026.107954","article-title":"Combined positive score using 28-8 predicts nivolumab efficacy in HNSCC","volume":"176","author":"Sato","year":"2026","journal-title":"Oral. Oncol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1002\/hed.26036","article-title":"Impact of PD-L1 expression and human papillomavirus status in anti-PD1\/PDL1 immunotherapy for head and neck squamous cell carcinoma-Systematic review and meta-analysis","volume":"42","author":"Patel","year":"2020","journal-title":"Head. Neck"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"107348","DOI":"10.1016\/j.oraloncology.2025.107348","article-title":"De-escalated surgery following neoadjuvant chemoimmunotherapy for locally advanced oral squamous cell carcinoma: A retrospective cohort study","volume":"165","author":"Cao","year":"2025","journal-title":"Oral. Oncol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2993","DOI":"10.21873\/invivo.14100","article-title":"The Role of Salvage Chemotherapy on Survival Outcomes Following Immune Checkpoint Inhibitor Therapy in Recurrent and\/or Metastatic Head and Neck Squamous Cell Carcinoma","volume":"39","author":"Abe","year":"2025","journal-title":"In Vivo"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1038\/s41416-019-0449-y","article-title":"Intratumor heterogeneity of PD-L1 expression in head and neck squamous cell carcinoma","volume":"120","author":"Rasmussen","year":"2019","journal-title":"Br. J. Cancer"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1007\/s00011-024-01905-5","article-title":"Comprehensive analysis of single cell and bulk RNA sequencing reveals the heterogeneity of melanoma tumor microenvironment and predicts the response of immunotherapy","volume":"73","author":"Zhang","year":"2024","journal-title":"Inflamm. Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"101471","DOI":"10.1016\/j.gendis.2024.101471","article-title":"Comprehensive analysis of immune subtype characterization on identification of potential cells and drugs to predict response to immune checkpoint inhibitors for hepatocellular carcinoma","volume":"12","author":"Lai","year":"2025","journal-title":"Genes Dis."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/11\/1845\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T17:19:56Z","timestamp":1780593596000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/11\/1845"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,4]]},"references-count":87,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["cancers18111845"],"URL":"https:\/\/doi.org\/10.3390\/cancers18111845","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,4]]}}}