Precision Translational Research for HPV-Positive and HPV-Negative Tonsillar Squamous Cell Carcinoma: Molecular Mechanisms, MRD Monitoring, and Individualized Therapeutic Optimization

Tonsillar squamous cell carcinoma represents the dominant and most clinically heterogeneous subsite of oropharyngeal squamous cell carcinoma (OPSCC), characterized by two distinct etiological subtypes driven by high-risk HPV infection or chronic tobacco/alcohol exposure. Over the past two decades, these two molecularly and clinically divergent subtypes have exhibited contradictory epidemiological trends, prognostic profiles, and therapeutic responses, creating a major bottleneck in standardized precision management of head and neck malignancies. HPV-positive tonsillar carcinoma predominantly affects young, non-smoking patients with superior overall survival and unique tumor biological characteristics, yet the core molecular and immune mechanisms driving its favorable prognosis remain poorly elucidated. Crucially, safe and validated treatment de-escalation strategies tailored to individual low-risk HPV-positive patients are still lacking, with unresolved conflicts between survival benefit and long-term iatrogenic functional impairment.In sharp contrast, HPV-negative tonsillar carcinoma, driven by tobacco and alcohol carcinogenesis, is characterized by high-grade genomic instability, immunosuppressive tumor microenvironment, inherent therapeutic resistance, and persistently dismal long-term survival. Despite conventional radical surgery, radiotherapy, and systemic chemotherapy, high rates of local recurrence and distant metastasis continue to plague clinical practice, while effective predictive biomarkers and targeted intervention strategies for this aggressive subtype remain underexplored. The profound biological discrepancy between HPV-positive and HPV-negative tonsillar cancer necessitates subtype-specific basic research, risk stratification systems, and therapeutic optimization frameworks, rather than generalized oropharyngeal cancer management protocols.In recent years, multi-omic sequencing, spatial immune microenvironment profiling, epigenetic modification analysis, and circulating biomarker-based liquid biopsy technologies have profoundly advanced our understanding of tonsillar cancer oncogenesis, subtype classification, and treatment resistance. Meanwhile, clinical paradigms including transoral robotic surgery (TORS)-based minimally invasive resection, individualized immunotherapy combination regimens, and MRD-guided dynamic treatment adjustment have reshaped the clinical workflow of tonsillar cancer management. However, a critical translational gap persists: most emerging molecular signatures and preclinical therapeutic targets lack prospective clinical validation, and clinically applicable tools for subtype-specific early diagnosis, recurrence prediction, minimal residual disease (MRD) surveillance, and precise treatment selection are still unavailable in routine clinical practice.This Research Topic focuses specifically on subtype-specific translational research of HPV-positive and HPV-negative tonsillar squamous cell carcinoma, aiming to address the unmet clinical need for precise stratification, dynamic monitoring, and individualized treatment optimization. It uniquely highlights the biological differences between the two etiological subtypes, prioritizes research that bridges preclinical molecular mechanisms and patient-centered clinical outcomes, and consolidates high-quality evidence to refine modern precision oncology strategies for tonsillar cancer. We invite original research, comprehensive reviews, systematic analyses, perspectives, and clinical reports that uncover subtype-specific pathogenic mechanisms, validate novel prognostic and predictive biomarkers, and optimize individualized surgical, radiotherapeutic, and systemic therapeutic regimens.We welcome manuscripts focusing on, but not limited to, the following subtype-specific and clinically oriented themes:• Subtype-specific genomic and multi-omic signatures for precise risk stratification, early diagnosis, and progression prediction in HPV-positive and HPV-negative tonsillar cancer• Technical advances and clinical validation of minimal residual disease (MRD) and minimal disseminated disease (MDD) for recurrence surveillance and treatment response evaluation in tonsillar carcinoma• Subtype-specific epigenetic reprogramming mechanisms driving tumor initiation, malignant progression, and therapeutic resistance in tonsillar squamous cell carcinoma• Spatial heterogeneity, immune evasion mechanisms, and subtype-specific tumor microenvironment landscapes of HPV-positive versus HPV-negative tonsillar cancer• Optimized combination immunotherapy strategies and resistance mechanisms for recurrent and metastatic tonsillar carcinoma stratified by HPV status• Key molecular drivers underlying therapeutic resistance in distinct tonsillar cancer subtypes and the development of novel targeted therapeutic strategies• Regulatory effects of the oral microbiome on subtype-specific tumor pathogenesis, immune microenvironment remodeling, and treatment response in tonsillar cancer• Population-level epidemiological changes and preventive effects of HPV vaccination on future HPV-associated tonsillar and oropharyngeal malignancies• Evidence-based evaluation, clinical controversies, and novel prospective paradigms of risk-adapted treatment de-escalation for low-risk HPV-positive tonsillar squamous cell carcinoma• Oncological safety, long-term functional preservation, and quality-of-life outcomes of TORS and minimally invasive surgery in subtype-stratified tonsillar cancer patientsThis Research Topic accepts Original Research, Review, Systematic Review, Mini Review, Clinical Trial, Perspective, Opinion, Case Report, and Brief Research Report, and Hypothesis and Theory articles. Manuscripts consisting solely of bioinformatics or computational analysis of publicly available genomic or transcriptomic databases without independent clinical cohort validation or in vitro/in vivo biological validation are outside the scope of this topic and will not be considered. Topic editors: Rui Wu, Wei Wang, Zheng Liang Source: https://www.frontiersin.org/research-topics/83222/precision-translational-research-for-hpv-positive-and-hpv-negative-tonsillar-squamous-cell-carcinoma-molecular-mechanisms-mrd-monitoring-and-individualized-therapeutic-optimization