{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T03:19:55Z","timestamp":1785727195471,"version":"3.56.0"},"reference-count":108,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Head and neck squamous cell carcinoma (HNSCC) is biologically and clinically dichotomous according to HPV status, a distinction that fundamentally dictates the design, implementation, and interpretation of liquid biopsy strategies. Conventional anatomical imaging lacks sufficient sensitivity for minimal residual disease (MRD) detection, contributing significantly to treatment failure and suboptimal clinical outcomes. This review provides a critical, evidence-based synthesis of the three principal circulating analytes, circulating tumor DNA (ctDNA), exosomes, and circulating tumor cells (CTCs), and their evolving roles in real-time, non-invasive molecular monitoring. Critically, the clinical readiness of these analytes differs substantially: while ctDNA, particularly HPV-related ctDNA, is approaching clinical validation for MRD detection and recurrence surveillance in HPV-positive HNSCC, exosomes and CTCs remain investigational tools hindered by ongoing technical challenges including lack of standardized assays, limited reproducibility across platforms, and insufficient prospective validation. We review how the presence of a clonal, virally derived DNA target in HPV-positive HNSCC contrasts with the heterogeneous somatic mutational landscape of HPV-negative tumors, necessitating divergent analytical platforms and yielding distinct clinical utility profiles for MRD detection and recurrence surveillance. We further outline a pragmatic translational pathway focused on assay standardization, particularly for exosomes and CTCs where this foundational work is most urgently needed, integration of complementary multimodal liquid biopsy approaches, and rigorously designed prospective interventional clinical trials to establish clinical utility. Collectively, these efforts aim to transition HNSCC management from reactive, anatomy-based surveillance to proactive, molecularly guided precision oncology, with the potential to improve therapeutic decision-making and patient outcomes.<\/jats:p>","DOI":"10.3390\/ijms27062847","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T17:02:43Z","timestamp":1774026163000},"page":"2847","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Liquid Biopsies in HNSCC: Current Landscape and Emerging Opportunities in the Era of HPV Stratification"],"prefix":"10.3390","volume":"27","author":[{"given":"Akshaya","family":"Poonepalle","sequence":"first","affiliation":[{"name":"Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianqiang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4972-1477","authenticated-orcid":false,"given":"Nabil F.","family":"Saba","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8747-4975","authenticated-orcid":false,"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Chemical, Materials and Biomedical Engineering, University of Georgia, Athens, GA 30602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1856-7289","authenticated-orcid":false,"given":"Yong","family":"Teng","sequence":"additional","affiliation":[{"name":"Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA"},{"name":"Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3329","DOI":"10.1158\/1078-0432.CCR-24-0590","article-title":"Personalized ctDNA for Monitoring Disease Status in Head and Neck Squamous Cell Carcinoma","volume":"30","author":"Hanna","year":"2024","journal-title":"Clin. Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/nrc.2018.11","article-title":"The molecular landscape of head and neck cancer","volume":"18","author":"Leemans","year":"2018","journal-title":"Nat. Rev. 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