{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T15:56:48Z","timestamp":1764086208828,"version":"3.45.0"},"reference-count":128,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FEDER\u2014Fundo Europeu de Desenvolimento Regional","award":["UIDB\/4255\/2020"],"award-info":[{"award-number":["UIDB\/4255\/2020"]}]},{"name":"FCT and FEDER","award":["IF\/00092\/2014\/CP1255\/CT0004","PRR-09\/C06-834I07\/2024.P11721","2024.18026.PEX"],"award-info":[{"award-number":["IF\/00092\/2014\/CP1255\/CT0004","PRR-09\/C06-834I07\/2024.P11721","2024.18026.PEX"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Oral and oropharyngeal squamous cell carcinomas (OSCC and OPSCC), two major sub-types of Head and Neck cancer, remain associated with significant morbidity and exhibit poor prognosis, with limited response to conventional therapies in advanced stages. Recent therapeutic strategies have increasingly focused on molecular targets involved in tumor proliferation, angiogenesis, and immune evasion. This overview provides a concise synthesis of targeted therapies under investigation or already in clinical use, including monoclonal antibodies against epidermal growth factor receptor (EGFR) (e.g., cetuximab) and immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab), as well as inhibitors of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) or agents targeting angiogenic and intracellular signaling pathways such as VEGF and mTOR. Alongside these novel agents, growing interest surrounds the repurposing of established pharmacological agents which appear to modulate tumor-related inflammation, metabolic dysregulation, and epithelial-to-mesenchymal transition. Metformin and statins, for instance, have demonstrated anti-proliferative and pro-apoptotic effects in preclinical OSCC models. Notably, recent evidence suggests that regular use of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, may improve survival specifically in patients with PIK3CA-altered Head and Neck tumors, potentially through modulation of the COX-2\/PGE2 axis. Although prospective evidence remains limited and somewhat heterogeneous, existing preclinical and observational studies suggest that these agents may improve survival and reduce treatment-related toxicity, further pointing to the relevance of molecular stratification in guiding future repurposing strategies. This article aims to map the current therapeutic landscape, highlighting both established molecular targets and emerging repositioned drugs in the management of OSCC and OPSCC.<\/jats:p>","DOI":"10.3390\/cancers17233761","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T15:29:47Z","timestamp":1764084587000},"page":"3761","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeted Therapies in Oral and Oropharyngeal Cancer: An Overview of Emerging and Repurposed Agents"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7249-181X","authenticated-orcid":false,"given":"Geetpriya","family":"Kaur","sequence":"first","affiliation":[{"name":"PerMed Research Group, RISE-Health, Faculty of Medicine, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"},{"name":"RISE-Health, Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"}]},{"given":"Neetu","family":"Sinha","sequence":"additional","affiliation":[{"name":"PerMed Research Group, RISE-Health, Faculty of Medicine, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"},{"name":"RISE-Health, Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1283-1042","authenticated-orcid":false,"given":"Nuno","family":"Vale","sequence":"additional","affiliation":[{"name":"PerMed Research Group, RISE-Health, Faculty of Medicine, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"},{"name":"RISE-Health, Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"Laboratory of Personalized Medicine, Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7628-8598","authenticated-orcid":false,"given":"Rui Amaral","family":"Mendes","sequence":"additional","affiliation":[{"name":"PerMed Research Group, RISE-Health, Faculty of Medicine, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"},{"name":"RISE-Health, Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"Department of Oral and Maxillofacial Medicine and Diagnostic Sciences, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106-7342, USA"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,25]]},"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","unstructured":"National Cancer Institute (2025, September 30). Head and Neck Cancers Fact Sheet, Available online: https:\/\/www.cancer.gov\/types\/head-and-neck\/head-neck-fact-sheet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1158\/1940-6207.CAPR-20-0096","article-title":"An Integrated Approach for Preventing Oral Cavity and Oropharyngeal Cancers: Two Etiologies with Distinct and Shared Mechanisms of Carcinogenesis","volume":"13","author":"Christensen","year":"2020","journal-title":"Cancer Prev. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s11912-022-01227-x","article-title":"State of Rehabilitation Research in the Head and Neck Cancer Population: Functional Impact vs. Impairment-Focused Outcomes","volume":"24","author":"Parke","year":"2022","journal-title":"Curr. Oncol. Rep."},{"key":"ref_5","unstructured":"National Academies of Sciences, Engineering and Medicine, Health and Medicine Division, Board on Health Care Services, and National Cancer Policy Forum (2025, September 30). Long-Term Survivorship Care After Cancer Treatment: Proceedings of a Workshop, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK538366\/."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4","DOI":"10.5737\/236880763314","article-title":"A Cancer Survivorship Model for Holistic Cancer Care and Research","volume":"33","author":"Anglade","year":"2023","journal-title":"Can. Oncol. Nurs. J."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Cabral, L.G.S., Martins, I.M., Paulo, E.P.A., Pomini, K.T., Poyet, J.L., and Maria, D.A. (2025). Molecular Mechanisms in the Carcinogenesis of Oral Squamous Cell Carcinoma: A Literature Review. Biomolecules, 15.","DOI":"10.3390\/biom15050621"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Barroso, L., Veiga, P., Melo, J.B., Carreira, I.M., and Ribeiro, I.P. (2025). Molecular and Genetic Pathogenesis of Oral Cancer: A Basis for Customized Diagnosis and Treatment. Biology, 14.","DOI":"10.3390\/biology14070842"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Constantin, M., Chifiriuc, M.C., Bleotu, C., Vrancianu, C.O., Cristian, R.-E., Bertesteanu, S.V., Grigore, R., and Bertesteanu, G. (2024). Molecular Pathways and Targeted Therapies in Head and Neck Cancers Pathogenesis. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1373821"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Li, Q., Li, Z., Luo, T., and Shi, H. (2022). Targeting the PI3K\/AKT\/mTOR and RAF\/MEK\/ERK Pathways for Cancer Therapy. Mol. Biomed., 3.","DOI":"10.1186\/s43556-022-00110-2"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/s41368-023-00249-w","article-title":"Oral Squamous Cell Carcinomas: State of the Field and Emerging Directions","volume":"15","author":"Tan","year":"2023","journal-title":"Int. J. Oral Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1111\/joim.20106","article-title":"The TP53 Tumor Suppressor Gene: From Molecular Biology to Clinical Investigations","volume":"298","author":"Baliakas","year":"2025","journal-title":"J. Intern. Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Capuozzo, M., Santorsola, M., Bocchetti, M., Perri, F., Cascella, M., Granata, V., Celotto, V., Gualillo, O., Cossu, A.M., and Nasti, G. (2022). p53: From Fundamental Biology to Clinical Applications in Cancer. Biology, 11.","DOI":"10.3390\/biology11091325"},{"key":"ref_14","first-page":"1289","article-title":"Regulation of Tumor Suppressor Gene CDKN2A and Encoded p16-INK4a Protein by Covalent Modifications","volume":"83","author":"Jiao","year":"2018","journal-title":"Biochemistry"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2136","DOI":"10.18632\/aging.204601","article-title":"The Cell Senescence Regulator p16 Is a Promising Cancer Prognostic and Immune Check-Point Inhibitor (ICI) Therapy Biomarker","volume":"15","author":"Tu","year":"2023","journal-title":"Aging"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Go\u0142\u0105bek, K., R\u0105czka, G., Ga\u017adzicka, J., Mi\u015bkiewicz-Orczyk, K., Zi\u0119ba, N., Krakowczyk, \u0141., Misio\u0142ek, M., and Strzelczyk, J.K. (2022). Expression Profiles of CDKN2A, MDM2, E2F2 and LTF Genes in Oral Squamous Cell Carcinoma. Biomedicines, 10.","DOI":"10.3390\/biomedicines10123011"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Guo, Z., Li, K., Ren, X., Wang, X., Yang, D., Ma, S., Zeng, X., and Zhang, P. (2025). The Role of the Tumor Microenvironment in HNSCC Resistance and Targeted Therapy. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1554835"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/s41392-025-02280-1","article-title":"Immune Evasion in Cancer: Mechanisms and Cutting-Edge Therapeutic Approaches","volume":"10","author":"Tufail","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1186\/s13046-021-01987-7","article-title":"Regulatory Mechanisms of Immune Checkpoints PD-L1 and CTLA-4 in Cancer","volume":"40","author":"Zhang","year":"2021","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e25895","DOI":"10.1016\/j.heliyon.2024.e25895","article-title":"Molecular Basis, Potential Biomarkers, and Future Prospects of OSCC and PD-1\/PD-L1 Related Immunotherapy Methods","volume":"10","author":"Cheng","year":"2024","journal-title":"Heliyon"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Arriola Ben\u00edtez, P.C., Fusco, M., Amorin, R., Pic\u00f3n, C.R., Piccioni, F., Victoria, L., Rizzo, M.M., and Malvicini, M. (2025). Unraveling the Role of Tumor-Infiltrating Immune Cells in Head and Neck Squamous Cell Carcinoma: Implications for Antitumor Immune Responses and Immunotherapy. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26136337"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"107145","DOI":"10.1016\/j.oraloncology.2024.107145","article-title":"Immunotherapeutic Strategies beyond the PD-1\/PD-L1 Pathway in Head and Neck Squamous Cell Carcinoma: A Scoping Review on Current Developments in Agents Targeting TIM-3, TIGIT, LAG-3, and VISTA","volume":"161","author":"Struckmeier","year":"2025","journal-title":"Oral Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Tiwari, R., Singh, V.K., Kumar, A., Mehrotra, S., Gautam, V., Neville, J.F., Bansal, V., Pathak, R., and Singh, A.K. (2025). Exploring Metabolic and Immunological Biomarkers for Oral Squamous Cell Carcinoma: Potential Targets for Precision Therapy. Biology, 14.","DOI":"10.3390\/biology14091109"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.immuni.2019.06.025","article-title":"Inflammation and Cancer: Triggers, Mechanisms, and Consequences","volume":"51","author":"Greten","year":"2019","journal-title":"Immunity"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Jiang, Y., Yang, W., Hu, J., and Tao, L. (2025). Editorial: The Tumor Microenvironment and Immunotherapy for Head and Neck Tumors. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1606787"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1186\/s12967-025-06583-3","article-title":"Targeting Inflammation in Cancer Therapy: From Mechanistic Insights to Emerging Therapeutic Approaches","volume":"23","author":"Bakrim","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4301","DOI":"10.2147\/JIR.S428358","article-title":"The Role of Inflammation-Associated Factors in Head and Neck Squamous Cell Carcinoma","volume":"16","author":"Li","year":"2023","journal-title":"J. Inflamm. Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Chen, S., Wu, X., Yang, Y., Xu, X., Xiong, X., and Meng, W. (2024). Increased Pathogenicity and Pro-Inflammatory Capabilities of Mucosal-Associated Invariant T Cells Involved in Oral Lichen Planus. BMC Oral Health, 24.","DOI":"10.1186\/s12903-024-04621-y"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Pugliese, G., Nitro, L., Allevi, F., Biglioli, F., Coccapani, M., Felisati, G., Ferella, F., Ghilardi, G., Montavoci, L., and Caretti, A. (2024). Can Serum and Saliva Inflammatory Cytokines Be Considered a Reliable Marker in Chronic Oral Graft-Versus-Host Disease Patients?. J. Pers. Med., 14.","DOI":"10.3390\/jpm14121122"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Wang, L., Zhang, L., Zhang, Z., Wu, P., Zhang, Y., and Chen, X. (2024). Advances in Targeting Tumor Microenvironment for Immunotherapy. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1472772"},{"key":"ref_31","first-page":"21","article-title":"Tumor Microenvironment-Driven Resistance to Immunotherapy in Non-Small Cell Lung Cancer: Strategies for Cold-to-Hot Tumor Transformation","volume":"8","author":"Yu","year":"2025","journal-title":"Cancer Drug Resist."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1186\/s12943-023-01827-6","article-title":"PI3K\/AKT\/mTOR Signaling Transduction Pathway and Targeted Therapies in Cancer","volume":"22","author":"Glaviano","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e70295","DOI":"10.1002\/mco2.70295","article-title":"PI3K\/AKT\/mTOR Axis in Cancer: From Pathogenesis to Treatment","volume":"6","author":"Jiang","year":"2025","journal-title":"MedComm"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/s41392-021-00828-5","article-title":"Targeting PI3K\/Akt Signal Transduction for Cancer Therapy","volume":"6","author":"He","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"9918379","DOI":"10.1155\/2021\/9918379","article-title":"Exploring the Crosstalk between Inflammation and Epithelial\u2013Mesenchymal Transition in Cancer","volume":"2021","author":"Chattopadhyay","year":"2021","journal-title":"Mediat. Inflamm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1186\/s12935-024-03357-7","article-title":"PI3K\/AKT Pathway as a Pivotal Regulator of Epithelial\u2013Mesenchymal Transition in Lung Tumor Cells","volume":"24","author":"Moghbeli","year":"2024","journal-title":"Cancer Cell Int."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"388","DOI":"10.5306\/wjco.v13.i5.388","article-title":"Immune Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinoma: A Systematic Review of Phase-3 Clinical Trials","volume":"13","author":"Poulose","year":"2022","journal-title":"World J. Clin. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1002\/lary.30971","article-title":"Immune Checkpoint Inhibitors Serve as the First-Line Treatment for Advanced Head and Neck Cancer","volume":"134","author":"Huang","year":"2024","journal-title":"Laryngoscope"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1080\/14728214.2020.1852215","article-title":"Emerging Immune Checkpoint Inhibitors for the Treatment of Head and Neck Cancers","volume":"25","author":"Green","year":"2020","journal-title":"Expert Opin. Emerg. Drugs"},{"key":"ref_40","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_41","doi-asserted-by":"crossref","first-page":"102938","DOI":"10.1016\/j.ctrv.2025.102938","article-title":"Management Approaches for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma after Anti-PD-1\/PD-L1 Immunotherapy","volume":"136","author":"Tahara","year":"2025","journal-title":"Cancer Treat. Rev."},{"key":"ref_42","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_43","doi-asserted-by":"crossref","unstructured":"Aboaid, H., Khalid, T., Hussain, A., Myat, Y.M., Nanda, R.K., Srinivasmurthy, R., Nguyen, K., Jones, D.T., Bigcas, J.L., and Thein, K.Z. (2025). Advances and Challenges in Immunotherapy in Head and Neck Cancer. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1596583"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Uppaluri, R., Lee, N.Y., Westra, W., Cohen, E.E.W., Haddad, R.I., Temam, S., Le Tourneau, C., Chernock, R., Safina, S., and Klochikhin, A. (2019). KEYNOTE-689: Phase 3 Study of Adjuvant and Neoadjuvant Pembrolizumab Combined with Standard of Care (SOC) in Patients with Resectable, Locally Advanced Head and Neck Squamous Cell Carcinoma. J. Clin. Oncol., 37.","DOI":"10.1200\/JCO.2019.37.15_suppl.TPS6090"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2572","DOI":"10.1200\/JCO-24-01580","article-title":"Randomized Phase II Study of Concurrent Versus Sequential Pembrolizumab in Combination with Chemoradiation in Locally Advanced Head and Neck Cancer","volume":"43","author":"Zandberg","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_46","unstructured":"Merck (2025, September 30). FDA Grants Priority Review to Merck\u2019s Application for KEYTRUDA (Pembrolizumab) Plus Standard of Care as Perioperative Treatment for Resectable Locally Advanced Head and Neck Squamous Cell Carcinoma. News Release, 25 February 2025. Available online: https:\/\/tinyurl.com\/2kmefvjn."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Clump, D.A., Zandberg, D.P., Skinner, H.D., Ohr, J., Fenton, M.J., Normolle, D.P., Beitler, J.J., Bauman, J.E., and Ferris, R.L. (2022). A Randomized Phase II Study Evaluating Concurrent or Sequential Fixed-Dose Immune Therapy in Combination with Cisplatin and Intensity-Modulated Radiotherapy in Intermediate- or High-Risk, Previously Untreated, Locally Advanced Head and Neck Cancer (LA SCCHN). J. Clin. Oncol., 40.","DOI":"10.1200\/JCO.2022.40.16_suppl.6007"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2166","DOI":"10.1200\/JCO.22.00332","article-title":"Nivolumab plus Ipilimumab Versus EXTREME Regimen as First-Line Treatment for Recurrent\/Metastatic Squamous Cell Carcinoma of the Head and Neck: The Final Results of CheckMate 651","volume":"41","author":"Haddad","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2548","DOI":"10.21037\/tcr-2024-2569","article-title":"Novel Combinations with Programmed Cell Death 1 Inhibitor for Incurable Recurrent\/Metastatic Head and Neck Squamous Cell Carcinoma (RM HNSCC): Is Cabozantinib a Front Runner?","volume":"14","author":"Bhateja","year":"2025","journal-title":"Transl. Cancer Res."},{"key":"ref_50","unstructured":"ClinicalTrials.gov (2025, September 30). Combination Study with Soluble LAG-3 Fusion Protein Eftilagimod Alpha (IMP321) and Pembrolizumab in Patients with Previously Untreated Unresectable or Metastatic NSCLC, or Recurrent PD-X Refractory NSCLC or With Recurrent or Metastatic HNSCC (TACTI-002), ID NCT03625323, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03625323."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"6029","DOI":"10.1200\/JCO.2023.41.16_suppl.6029","article-title":"Final Results from TACTI-002 Part C: A Phase II Study of Eftilagimod Alpha (Soluble LAG-3 Protein) and Pembrolizumab in Patients with Metastatic 2nd Line Head and Neck Squamous Cell Carcinoma Unselected for PD-L1","volume":"41","author":"Felip","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_52","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_53","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1186\/s12943-023-01800-3","article-title":"Co-inhibition of TIGIT and PD-1\/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials","volume":"22","author":"Chu","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"105472","DOI":"10.1016\/j.oraloncology.2021.105472","article-title":"TIGIT\/CD155 Blockade Enhances Anti-PD-L1 Therapy in Head and Neck Squamous Cell Carcinoma by Targeting Myeloid-Derived Suppressor Cells","volume":"121","author":"Mao","year":"2021","journal-title":"Oral Oncol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Morch\u00f3n-Araujo, D., Catani, G., Mirallas, O., Pretelli, G., S\u00e1nchez-P\u00e9rez, V., Vieito, M., Bra\u00f1a, I., Pujol-Borrell, R., Garralda, E., and Hernando-Calvo, A. (2025). Emerging Immunotherapy Targets in Early Drug Development. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26115394"},{"key":"ref_56","unstructured":"ClinicalTrials.gov (2025, September 30). A Study of Pembrolizumab (MK-3475) for First Line Treatment of Recurrent or Metastatic Squamous Cell Cancer of the Head and Neck (MK-3475-048\/KEYNOTE-048), ID NCT02358031, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02358031."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Sun, F., and Colevas, A.D. (2025). Update: Immunotherapeutic Strategies in HPV-Associated Head and Neck Squamous Cell Carcinoma. Viruses, 17.","DOI":"10.3390\/v17050712"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Jiang, B., Elkashif, A., Coulter, J.A., Dunne, N.J., and McCarthy, H.O. (2024). Immunotherapy for HPV Negative Head and Neck Squamous Cell Carcinoma. Biochim. Biophys. Acta Rev. Cancer, 1879.","DOI":"10.1016\/j.bbcan.2024.189138"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1007\/s10555-025-10274-2","article-title":"Tissue-Agnostic Biomarkers in Solid Tumors: Current Approvals and Emerging Candidates","volume":"44","author":"Kim","year":"2025","journal-title":"Cancer Metastasis Rev."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e003026","DOI":"10.1136\/jitc-2021-003026","article-title":"Influence of Tumor Mutational Burden, Inflammatory Gene Expression Profile, and PD-L1 Expression on Response to Pembrolizumab in Head and Neck Squamous Cell Carcinoma","volume":"10","author":"Haddad","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s13402-020-00519-3","article-title":"Modeling of the Immune Response in the Pathogenesis of Solid Tumors and Its Prognostic Significance","volume":"43","author":"Zadka","year":"2020","journal-title":"Cell Oncol."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Nicoar\u0103, A., Roi, C., Roi, A., Motofelea, A.C., Rakitovan, M., Zar\u0103, F., and Rivi\u0219, M. (2024). Systemic Immune-Inflammatory Index and Other Inflammatory Marker Variations in Oral Squamous Cell Carcinoma Management. Medicina, 60.","DOI":"10.3390\/medicina60111840"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Sutera, S., Furch\u00ec, O.A., and Pentenero, M. (2025). Investigating Tumor-Infiltrating Lymphocytes in the Microenvironment of Oral Squamous Cell Carcinoma (OSCC) and Oral Potentially Malignant Disorders (OPMDs): Can They Shift Our Perspective? A Scoping Review. J. Clin. Med., 14.","DOI":"10.3390\/jcm14020606"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/s41392-024-01979-x","article-title":"Cold and Hot Tumors: From Molecular Mechanisms to Targeted Therapy","volume":"9","author":"Wu","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Kaufman, N.E.M., Dhingra, S., Jois, S.D., and Vicente, M.d.G.H. (2021). Molecular Targeting of Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR). Molecules, 26.","DOI":"10.3390\/molecules26041076"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Purba, E.R., Saita, E.-i., and Maruyama, I.N. (2017). Activation of the EGF Receptor by Ligand Binding and Oncogenic Mutations: The \u201cRotation Model\u201d. Cells, 6.","DOI":"10.20944\/preprints201705.0212.v1"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"253","DOI":"10.3390\/neuroglia4040018","article-title":"The Signaling of Neuregulin-Epidermal Growth Factor Receptors and Its Impact on the Nervous System","volume":"4","author":"Tagliaferro","year":"2023","journal-title":"Neuroglia"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Abouelkheer, Y., and Bhatia, A. (2025). Head and Neck Cancer\u2014Emerging Targeted Therapies. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1640960"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Hallaji, M., Allahyari, M., Teimoori-Toolabi, L., Yasami-Khiabani, S., Golkar, M., and Fard-Esfahani, P. (2025). Targeted Cancer Treatment Using a Novel EGFR-Specific Fc-Fusion Peptide Based on GE11 Peptide. Sci. Rep., 15.","DOI":"10.1038\/s41598-025-89143-5"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Pannunzio, S., Di Bello, A., Occhipinti, D., Scala, A., Messina, G., Valente, G., Quirino, M., Di Salvatore, M., Tortora, G., and Cassano, A. (2024). Multimodality Treatment in Recurrent\/Metastatic Squamous Cell Carcinoma of Head and Neck: Current Therapy, Challenges, and Future Perspectives. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1288695"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.5114\/aoms.2019.86712","article-title":"Induction Chemotherapy Plus Nimotuzumab Followed by Concurrent Chemoradiotherapy for Advanced Nasopharyngeal Carcinoma","volume":"17","author":"Song","year":"2021","journal-title":"Arch. Med. Sci."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Meng, G., Zhang, D., Zhao, Y., Mao, M., Shen, K., Wang, X., and Bi, C. (2024). Nimotuzumab Combined with Radiotherapy \u00b1 Chemotherapy for Definitive Treatment of Locally Advanced Squamous Cell Carcinoma of Head and Neck: A Meta-analysis of Randomized Controlled Trials. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1380428"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Cui, J.-W., Li, Y., Yang, Y., Yang, H.-K., Dong, J.-M., Xiao, Z.-H., He, X., Guo, J.-H., Wang, R.-Q., and Dai, B. (2024). Tumor Immunotherapy Resistance: Revealing the Mechanism of PD-1\/PD-L1-Mediated Tumor Immune Escape. Biomed. Pharmacother., 171.","DOI":"10.1016\/j.biopha.2024.116203"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Qiao, X.W., Jiang, J., Pang, X., Huang, M.C., Tang, Y.J., Liang, X.H., and Tang, Y.L. (2020). The Evolving Landscape of PD-1\/PD-L1 Pathway in Head and Neck Cancer. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01721"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"3471","DOI":"10.31557\/APJCP.2024.25.10.3471","article-title":"The Expression of PD-L1 and PD-1 in the Microenvironment of Oral Squamous Cell Carcinoma","volume":"25","author":"Wahabi","year":"2024","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Zervanos, D.-I., Galatou, E., Miliotou, A.N., Theodoroula, N.F., Grigoriadis, N., and Vizirianakis, I.S. (2025). Assessing the Pharmacological and Pharmacogenomic Data of PD-1\/PD-L1 Inhibitors to Enhance Cancer Immunotherapy Outcomes in the Clinical Setting. Future Pharmacol., 5.","DOI":"10.20944\/preprints202506.2039.v1"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41392-024-02080-z","article-title":"Cyclin-Dependent Protein Kinases and Cell Cycle Regulation in Biology and Disease","volume":"10","author":"Pellarin","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1002\/ijc.20663","article-title":"Identification of Differentially Expressed Genes in Oral Squamous Cell Carcinoma (OSCC): Overexpression of NPM, CDK1, NDRG1, and Underexpression of CHES1","volume":"114","author":"Chang","year":"2005","journal-title":"Int. J. Cancer"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e7","DOI":"10.4317\/medoral.19841","article-title":"The Clinical Significance of CDK1 Expression in Oral Squamous Cell Carcinoma","volume":"20","author":"Chen","year":"2015","journal-title":"Med. Oral Patol. Oral Cir. Bucal"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1111\/jop.12903","article-title":"The Role of Cyclin-Dependent Kinases in Oral Potentially Malignant Disorders and Oral Squamous Cell Carcinoma","volume":"48","author":"Kujan","year":"2019","journal-title":"J. Oral Pathol. Med."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Zhang, R., Yao, Y., Gao, H., and Hu, X. (2024). Mechanisms of Angiogenesis in Tumour. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1359069"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Pomella, S., Melaiu, O., Dri, M., Martelli, M., Gargari, M., and Barillari, G. (2024). Effects of Angiogenic Factors on the Epithelial-to-Mesenchymal Transition and Their Impact on the Onset and Progression of Oral Squamous Cell Carcinoma: An Overview. Cells, 13.","DOI":"10.3390\/cells13151294"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1186\/s12935-024-03476-1","article-title":"Extracellular Vesicle-Bound VEGF in Oral Squamous Cell Carcinoma and Its Role in Resistance to Bevacizumab Therapy","volume":"24","author":"Zhou","year":"2024","journal-title":"Cancer Cell Int."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.radonc.2013.07.003","article-title":"Sorafenib sensitizes head and neck squamous cell carcinoma cells to ionizing radiation","volume":"109","author":"Laban","year":"2013","journal-title":"Radiother. Oncol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"26","DOI":"10.3892\/ijo.2023.5474","article-title":"Dual Inhibition of EGFR and VEGF: An Effective Approach to the Treatment of Advanced Non-Small Cell Lung Cancer with EGFR Mutation (Review)","volume":"62","author":"Wang","year":"2023","journal-title":"Int. J. Oncol."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Yonesi, A., Tomihara, K., Takatsuka, D., Tachinami, H., Yamazaki, M., Jadidi, A.R., Takaichi, M., Imaue, S., Fujiwara, K., and Yamada, S.I. (2024). Rapamycin Induces Phenotypic Alterations in Oral Cancer Cells That May Facilitate Antitumor T Cell Responses. Biomedicines, 12.","DOI":"10.3390\/biomedicines12051078"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/1758-3284-3-22","article-title":"Mammalian Target of Rapamycin and Head and Neck Squamous Cell Carcinoma","volume":"3","author":"Liao","year":"2011","journal-title":"Head Neck Oncol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1186\/s12935-022-02706-8","article-title":"Recent Advances and Limitations of mTOR Inhibitors in the Treatment of Cancer","volume":"22","author":"Ali","year":"2022","journal-title":"Cancer Cell Int."},{"key":"ref_89","unstructured":"(2025, September 30). Advances in mTOR Inhibitors. [Internet]. June 2022. Available online: https:\/\/www.bocsci.com\/blog\/advances-in-mtor-inhibitors."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s12962-023-00420-4","article-title":"Everolimus and Temsirolimus Are Not the Same Second-Line in Metastatic Renal Cell Carcinoma: A Systematic Review and Meta-Analysis","volume":"21","author":"Goudarzi","year":"2023","journal-title":"Cost Eff. Resour. Alloc."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.oraloncology.2012.12.016","article-title":"A Phase II Study of Temsirolimus and Erlotinib in Patients with Recurrent and\/or Metastatic, Platinum-Refractory Head and Neck Squamous Cell Carcinoma","volume":"49","author":"Bauman","year":"2013","journal-title":"Oral Oncol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"85","DOI":"10.18632\/oncotarget.28355","article-title":"Everolimus Downregulates STAT3\/HIF-1\u03b1\/VEGF Pathway to Inhibit Angiogenesis and Lymphangiogenesis in TP53 Mutant Head and Neck Squamous Cell Carcinoma (HNSCC)","volume":"14","author":"Alam","year":"2023","journal-title":"Oncotarget"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Li, C., Dong, X., and Li, B. (2024). Tumor Microenvironment in Oral Squamous Cell Carcinoma. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1485174"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.32604\/or.2025.064010","article-title":"Dysregulated PI3K\/AKT Signaling in Oral Squamous Cell Carcinoma: The Tumor Microenvironment and Epigenetic Modifiers as Key Drivers","volume":"33","author":"Veerasamy","year":"2025","journal-title":"Oncol. Res."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Amengual-Cladera, E., Morla-Barcelo, P.M., Mor\u00e1n-Costoya, A., Sastre-Serra, J., Pons, D.G., Valle, A., Roca, P., and Nadal-Serrano, M. (2024). Metformin: From Diabetes to Cancer\u2014Unveiling Molecular Mechanisms and Therapeutic Strategies. Biology, 13.","DOI":"10.20944\/preprints202403.1343.v1"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1210\/endrev\/bnaa023","article-title":"Cellular and Molecular Mechanisms of Metformin Action","volume":"42","author":"LaMoia","year":"2021","journal-title":"Endocr. Rev."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"182","DOI":"10.3923\/ijp.2022.182.189","article-title":"Metformin Induces Cytotoxicity in Oral Squamous Cell Carcinoma Cells by Targeting CCN1\/Akt-Axis","volume":"18","author":"Zhang","year":"2022","journal-title":"Int. J. Pharmacol."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Li, J.H., Hsin, P.Y., Hsiao, Y.C., Chen, B.J., Zhuang, Z.Y., Lee, C.W., Lee, W.J., Vo, T.T.T., Tseng, C.F., and Tseng, S.F. (2024). A Narrative Review: Repurposing Metformin as a Potential Therapeutic Agent for Oral Cancer. Cancers, 16.","DOI":"10.3390\/cancers16173017"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"121274","DOI":"10.1016\/j.lfs.2022.121274","article-title":"Metformin Inhibits Oral Squamous Cell Carcinoma Progression through Regulating RNA Alternative Splicing","volume":"315","author":"Ji","year":"2023","journal-title":"Life Sci."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Qi, X., Xu, W., Xie, J., Wang, Y., Han, S., Wei, Z., Ni, Y., Dong, Y., and Han, W. (2016). Metformin Sensitizes the Response of Oral Squamous Cell Carcinoma to Cisplatin Treatment through Inhibition of NF-\u03baB\/HIF-1\u03b1 Signal Axis. Sci. Rep., 6.","DOI":"10.1038\/srep35788"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Zhao, W., Chen, C., Zhou, J., Chen, X., Cai, K., Shen, M., Chen, X., Jiang, L., and Wang, G. (2022). Inhibition of Autophagy Promotes the Anti-Tumor Effect of Metformin in Oral Squamous Cell Carcinoma. Cancers, 14.","DOI":"10.3390\/cancers14174185"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1186\/s12967-023-04263-8","article-title":"Metformin and Cancer Hallmarks: Shedding New Lights on Therapeutic Repurposing","volume":"21","author":"Hua","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Dongoran, R., Wang, K.-H., Lin, T.-J., Yuan, T.-C., and Liu, C.-H. (2020). Anti-Proliferative Effect of Statins Is Mediated by DNMT1 Inhibition and p21 Expression in OSCC Cells. Cancers, 12.","DOI":"10.3390\/cancers12082084"},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Spoerl, S., Gerken, M., Fischer, R., Spoerl, S., Kirschneck, C., Wolf, S., Taxis, J., Ludwig, N., Biermann, N., and Reichert, T.E. (2023). Statin Use Ameliorates Survival in Oral Squamous Cell Carcinoma\u2014Data from a Population-Based Cohort Study Applying Propensity Score Matching. Biomedicines, 11.","DOI":"10.3390\/biomedicines11020369"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Ricco, N., and Kron, S.J. (2023). Statins in Cancer Prevention and Therapy. Cancers, 15.","DOI":"10.3390\/cancers15153948"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1038\/s41419-022-04610-5","article-title":"Targeting CCL2-CCR4 Axis Suppresses Cell Migration of Head and Neck Squamous Cell Carcinoma","volume":"13","author":"Ling","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.oraloncology.2019.01.025","article-title":"Atorvastatin Increases Oxidative Stress and Inhibits Cell Migration of Oral Squamous Cell Carcinoma In Vitro","volume":"90","author":"Lotierzo","year":"2019","journal-title":"Oral Oncol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.job.2023.08.006","article-title":"Simvastatin Inhibits Proliferation and Promotes Apoptosis of Oral Squamous Cell Carcinoma through KLF2 Signal","volume":"65","author":"Kou","year":"2023","journal-title":"J. Oral Biosci."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Wang, S., Shi, M., Wang, H., Zeng, X., Zhang, D., Zhang, Z., Xu, Z., and Li, Y. (2025). Effects on Oral Squamous Carcinoma Cell Lines and Their Mechanisms of Pyrazole N-Aryl Sulfonate: A Novel Class of Selective Cyclooxygenase-2 Inhibitors. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26188906"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/j.identj.2024.06.014","article-title":"Blocking \u03b2\u2082-AR and Inhibiting COX-2: A Promising Approach to Suppress OSCC Development","volume":"75","author":"Huang","year":"2025","journal-title":"Int. Dent. J."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Nasry, W.H.S., and Martin, C.K. (2021). Intersecting Mechanisms of Hypoxia and Prostaglandin E\u2082-Mediated Inflammation in the Comparative Biology of Oral Squamous Cell Carcinoma. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.539361"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.freeradbiomed.2024.12.035","article-title":"Dichloroacetate and Chloroquine in Combination with Arsenite Suppress ROS-Induced Oral Squamous Cell Carcinoma (OSCC) Development and Improve BALB\/c Mice Survival","volume":"227","author":"Benbelkacem","year":"2025","journal-title":"Free Radic. Biol. Med."},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Iglesias-Corral, D., Garc\u00eda-Valles, P., Arroyo-Garrapucho, N., Bueno-Mart\u00ednez, E., Ruiz-Robles, J.M., Ovejero-S\u00e1nchez, M., Gonz\u00e1lez-Sarmiento, R., and Herrero, A.B. (2024). Chloroquine-Induced DNA Damage Synergizes with DNA Repair Inhibitors Causing Cancer Cell Death. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1390518"},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Faraji-Barhagh, A., Jahandar-Lashaki, S., Esfahlan, R.J., and Alizadeh, E. (2025). Current Nano Drug Delivery Systems for Targeting Head and Neck Squamous Cell Carcinoma Microenvironment: A Narrative Review. Mol. Biol. Rep., 52.","DOI":"10.1007\/s11033-025-10462-x"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2138","DOI":"10.1002\/tox.23328","article-title":"Attenuation of Chloroquine and Hydroxychloroquine on the Invasive Potential of Bladder Cancer through Targeting Matrix Metalloproteinase 2 Expression","volume":"36","author":"Chou","year":"2021","journal-title":"Environ. Toxicol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/s41419-023-06405-8","article-title":"Antitumour Effect of the Mitochondrial Complex III Inhibitor Atovaquone in Combination with Anti-PD-L1 Therapy in Mouse Cancer Models","volume":"15","author":"Puliyadi","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"34084","DOI":"10.18632\/oncotarget.9122","article-title":"Repurposing Atovaquone: Targeting Mitochondrial Complex III and OXPHOS to Eradicate Cancer Stem Cells","volume":"7","author":"Fiorillo","year":"2016","journal-title":"Oncotarget"},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Kapur, A., Mehta, P., Simmons, A.D., Ericksen, S.S., Mehta, G., Palecek, S.P., Felder, M., Stenerson, Z., Nayak, A., and Dominguez, J.M.A. (2022). Atovaquone: An Inhibitor of Oxidative Phosphorylation as Studied in Gynecologic Cancers. Cancers, 14.","DOI":"10.3390\/cancers14092297"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1097\/CEJ.0000000000000626","article-title":"Can Propranolol Act as a Chemopreventive Agent during Oral Carcinogenesis? An Experimental Animal Study","volume":"30","author":"Wagner","year":"2021","journal-title":"Eur. J. Cancer Prev."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"804","DOI":"10.3892\/ol.2021.13065","article-title":"\u03b2\u2082 Adrenergic Receptor Expression and the Effects of Norepinephrine and Propranolol on Various Head and Neck Cancer Subtypes","volume":"22","author":"Kwon","year":"2021","journal-title":"Oncol. Lett."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"117816","DOI":"10.1016\/j.ejmech.2025.117816","article-title":"An Exploration of Molecular Signaling in Drug Reprocessing for Oral Squamous Cell Carcinoma","volume":"295","author":"Nakhaei","year":"2025","journal-title":"Eur. J. Med. Chem."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1080\/14737140.2021.1915136","article-title":"Development of CpG Oligodeoxynucleotide TLR9 Agonists in Anti-Cancer Therapy","volume":"21","author":"Jin","year":"2021","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"2578","DOI":"10.1016\/j.apsb.2021.09.030","article-title":"Self-Assembling Protein Nanocarrier for Selective Delivery of Cytotoxic Polypeptides to CXCR4\u207a Head and Neck Squamous Cell Carcinoma Tumors","volume":"12","author":"Casanova","year":"2022","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"4829","DOI":"10.1038\/s41467-022-31859-3","article-title":"A Nanoengineered Topical Transmucosal Cisplatin Delivery System Induces Anti-Tumor Response in Animal Models and Patients with Oral Cancer","volume":"13","author":"Goldberg","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"101838","DOI":"10.1016\/j.tranon.2023.101838","article-title":"Nanostructures for Site-Specific Delivery of Oxaliplatin Cancer Therapy: Versatile Nanoplatforms in Synergistic Cancer Therapy","volume":"39","author":"Bagheri","year":"2024","journal-title":"Transl. Oncol."},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Du, S., Guan, Y., Xie, A., Yan, Z., Gao, S., Li, W., Rao, L., Chen, X., and Chen, T. (2023). Extracellular Vesicles: A Rising Star for Therapeutics and Drug Delivery. J. Nanobiotechnol., 21.","DOI":"10.1186\/s12951-023-01973-5"},{"key":"ref_127","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Liu, J., Liu, S., Yu, L., Liu, S., Li, M., and Jin, F. (2023). Extracellular Vesicles in Oral Squamous Cell Carcinoma: Current Progress and Future Prospect. Front. Bioeng. Biotechnol., 11.","DOI":"10.3389\/fbioe.2023.1149662"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"107751","DOI":"10.1016\/j.phrs.2025.107751","article-title":"Extracellular Vesicles as Nature\u2019s Nano Carriers in Cancer Therapy: Insights towards Preclinical Studies and Clinical Applications","volume":"217","author":"Wu","year":"2025","journal-title":"Pharmacol. Res."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/23\/3761\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T15:42:11Z","timestamp":1764085331000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/23\/3761"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,25]]},"references-count":128,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["cancers17233761"],"URL":"https:\/\/doi.org\/10.3390\/cancers17233761","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,25]]}}}