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Results for “head and neck squamous cell carcinoma (HNSCC)”

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PubMed2026

Identification of a novel human gut microbes and microbial metabolites related genes signature for prognostic implication in head and neck squamous carcinomas.

BACKGROUND: The gut microbiota acts as a critical driver influencing the pathogenesis, therapeutic response, and clinical outcomes across various cancer types. This study aimed to investigate the prognostic value of human gut microbes and microbial metabolites related genes (HGMMMRGs) in head and neck squamous cell carcinoma (HNSCC). METHODS: We constructed a prognostic risk model comprising 19 core HGMMMRGs using LASSO penalized regression and a multivariate Cox proportional hazards model. The predictive performance of the model was evaluated through Kaplan-Meier analysis, receiver operating characteristic (ROC) curves, nomograms, and concordance index. In addition, functional enrichment analysis was performed on the differentially expressed risk genes. Furthermore, the relationship between the immune microenvironment of HNSCC and the risk diagnostic model was examined. Western blot analysis was used to assess the expression levels of IL10 in both HNSCC tissues and adjacent normal tissues. Finally, the correlation between IL10 and the gut microbiota was explored. RESULTS: This study developed a risk score model integrating 19 HGMMMRG genes, which can serve as a tool to guide prognosis and immune microenvironment assessment in HNSCC patients. Survival analysis showed that patients in the high-risk group had significantly worse outcomes (P < 0.05). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed significant enrichment of differentially expressed genes (DRLs) and immune-related pathways. Western blot analysis further confirmed that IL10 was highly expressed in HNSCC, and the abundance of Faecalibacterium prausnitzii and Enterococcus durans colonies was correlated with IL10 expression. CONCLUSION: We developed a prognostic model for HGMMMRGs that can be effectively used to predict OS in patients with HNSCC. Second, Faecalibacterium prausnitzii and Enterococcus durans can influence the prognosis of patients with HNSCC by mediating the expression IL10 and thereby affecting the prognosis of HNSCC patients. Thus, human gut microbes and microbial metabolite-related genes may be another promising strategy for the treatment of patients with HNSCC.

HNSCC↗

PubMed2026

Response-adapted surgical de-escalation following neoadjuvant immunotherapy in resectable mucosal HNSCC A systematic review and meta-analysis.

INTRODUCTION: Recent encouraging outcomes with neoadjuvant immune checkpoint inhibitors (ICIs) in mucosal head and neck squamous cell carcinoma (HNSCC) have generated interest in surgical de-escalation. However, the oncologic safety of response-adapted surgery (RAS) and its ability to achieve survival outcomes comparable to baseline-planned surgery (BPS) remain uncertain. METHODS: A systematic search of the PubMed, EMBASE, Cochrane Library, and the Clinical Trials Registry for studies of neoadjuvant ICIs, with or without chemotherapy, in resectable mucosal HNSCC, that explicitly report surgical extent, between 2020-2025 was performed. Two independent reviewers extracted data following PRISMA guidelines. Main outcomes included major pathologic response (MPR), pathologic complete response (pCR), event-free survival (EFS), and overall survival (OS). Study-level proportions were pooled by random effects models. Heterogeneity was assessed by the I2 statistic. RESULTS: The comparative analysis consisted of 4 RAS studies (involving 202 patients) and 11 BPS studies (403 patients). The pooled overall EFS was 83.3% (76.9-88.2) for the former and 82% (75.2-87.2) for the latter (P=.751), and the respective pooled OS was 92.3% (87.5-95.3) and 91.4% (80.3-96.5) (P=.839). The pooled pCR rate was 41.7% (95% CI 5.4-48.4; I2=.0) for RAS and 19.8% (95%CI 13.3-29.6; I2=.62) for BPS (P=.001), while the MPR was not significantly different (59.6%, versus 48.5%, P=.245). RAS was associated with greater organ preservation and reduced need for mandibulectomy and free-flap reconstruction. CONCLUSIONS: RAS following neoadjuvant ICIs in mucosal HNSCC may enable surgical de-escalation with preserved oncologic outcomes and improved function in selected patients. Larger prospective studies are warranted.

Humans↗

PubMed2026

Regulation of the lncRNA NEAT1 by p53-ΔNp63 crosstalk modulates the DNA damage response and therapeutic efficacy in HNSCC.

Head and neck squamous cell carcinomas (HNSCCs) are characterized by recurrent genetic alterations, including the inactivation of the tumor suppressor TP53 gene and dysregulation of the TP63 gene. The TP63 gene encodes multiple isoforms, among which the N-terminal truncated isoform ΔNp63 is fundamental for the integrity of stratified epithelial tissues. We previously demonstrated that ΔNp63 represses the expression of the lncRNA NEAT1. Here, we investigated the functional crosstalk between p53 and ΔNp63 in modulating NEAT1 expression following genotoxic stress. We found that upon genotoxic insults, p53 activation and the concomitant downregulation of ΔNp63 promote NEAT1 transcription. In p53-proficient HNSCC cells, NEAT1 targeting leads to increased DNA damage, highlighting its potential role in maintaining genomic stability and facilitating efficient DNA repair. Importantly, we showed that histone deacetylase inhibitors (HDACis) upregulate NEAT1 expression independently of p53, and NEAT1 silencing enhances HDACis-induced DNA damage. Overall, our findings establish NEAT1 as an early regulator of the DNA damage response in HNSCCs and suggest that combining NEAT1 targeting with HDAC inhibition may potentiate therapeutic efficacy, particularly in TP53-mutant HNSCCs.

DNA damage↗

PubMed2026

De-escalation of radiotherapy in HPV-negative non-nasopharyngeal head and neck squamous cell carcinoma: a systematic review.

BACKGROUND: Definitive and postoperative radiotherapy are central components of treatment for head and neck squamous cell carcinoma (HNSCC) but are associated with significant toxicities that can impair long-term function and quality of life. De-escalation strategies, aiming to reduce treatment-related morbidity while maintaining tumor control, have attracted increasing interest. However, most research has focused on HPV-positive oropharyngeal carcinoma. Systematic evidence for HPV-negative disease remains limited. METHODS: PubMed and EMBASE were searched for prospective studies investigating radio(chemo)therapy de-escalation in HPV-negative, HPV-unspecified, or mixed non-nasopharyngeal HNSCC populations. CLINICALTRIALS: gov was searched for ongoing prospective trials. Data extraction and verification were performed independently by three investigators. RESULTS: Screening of 3156 records identified 14 published prospective studies, 10 in the definitive and four in the postoperative setting. Strategies included reduction or omission of elective nodal volumes, dose reduction, and combined approaches. Additionally, 23 ongoing prospective trials were identified. Across studies, elective nodal failure rates were consistently low (0-4.6%), with most recurrences occurring within high-dose volumes rather than de-escalated elective regions. Randomized evidence for elective nodal dose reduction is mixed: two trials maintained regional control and reduced acute toxicity, whereas another was stopped for futility. CONCLUSION: Available evidence on de-escalation in HPV-negative HNSCC is limited, derived primarily from small, heterogeneous phase II studies with mixed HPV populations. Although data are promising in selected settings, notably for elective nodal control, the randomized evidence for elective nodal dose reduction is conflicting, and further adequately designed prospective randomized trials are required.

Humans↗

PubMed2026

Construction of a new predictive model in head and neck squamous cell carcinoma based on the investigation of extracellular matrix-associated genes.

A key aspect influencing immune cell infiltration is the composition of the extracellular matrix (ECM). Therefore, investigating the association between ECM-associated proteins and immune cell infiltration is key for the identification of new biomarkers to distinguish 'immune-hot' solid tumors and predict patient prognosis. A total of 513 head and neck squamous cell carcinoma (HNSCC) cases as training samples from The Cancer Genome Atlas and an additional 270 as testing samples from the Gene Expression Omnibus were obtained for use in the present study. Using a single-sample Gene Set Enrichment Analysis method, the 513 training samples were divided into Cluster 1 and Cluster 2. Subsequently, the present analysis uncovered 1,573 differentially expressed genes distinguishing the two clusters. After performing an intersection analysis with 751 ECM-associated genes, 103 differentially expressed ECM-associated genes were identified. Least absolute shrinkage and selection operator-Cox and multivariate Cox regression analyses were employed to identify candidate ECM risk genes (P<0.05) and to construct a predictive model. Finally, a nomogram and a three gene (cerebellin 2, galectin-10 and cathepsin G) predictive model were developed. Therefore, the present prognostic risk score model can evaluate the immune infiltration, predict the prognosis of HNSCC, and potentially guide more personalized immunotherapy interventions.

extracellular matrix↗

PubMed2025

Development and validation of a novel risk stratification signature derived from migrasome and tumor microenvironment-related genes for molecular subtyping and improving clinical outcomes in head and neck squamous cell carcinoma.

BACKGROUND: The tumor microenvironment (TME) and migrasomes released by tumor cells significantly influence carcinogenesis and immune evasion. However, our understanding of the prognostic and therapeutic implications of migrasome and tumor microenvironment-related genes (mtmRGs) in head and neck squamous cell carcinoma (HNSCC) remains limited. METHODS: We explored the relationship between mtmRGs and HNSCC prognosis by utilizing The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Subsequently, we developed an innovative prognostic signature, and assessed its prognostic significance using the Kaplan-Meier method, time-dependent receiver operating characteristic (ROC), and Cox regression analyses. To explore the underlying mechanisms, we conducted gene set variation analysis (GSVA), gene set enrichment analysis (GESA), and immune infiltration analysis. A nomogram was developed to estimate the overall survival (OS) rates for HNSCC patients. Lastly, we chose P4HA1, which was part of the signature, for additional experimental validation in vitro and in vivo. RESULTS: The mtmRGs signature effectively classifies HNSCC patients into two distinct risk subgroups, with the high-risk cohort demonstrating significantly poorer OS. The risk score serves as an independent prognostic factor for HNSCC patients; those with lower risk scores are more likely to exhibit favorable responses to immunotherapy, particularly with CTLA4 inhibitors. Furthermore, a lower risk score is significantly correlated with the sensitivity of HNSCC patients to cyclophosphamide, gemcitabine, and axitinib. CONCLUSION: This study presents an innovative gene signature associated with mtmRGs, which may be utilized both for predicting survival and directing personalized chemotherapy and immunotherapy regiments for patients with HNSCC.

Humans↗

PubMed2026

Multi-omics identification and functional validation of signal regulatory protein gamma as a prognostic biomarker and immune regulator in head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) comprises biologically diverse tumors, and durable responses to immune-checkpoint blockade are achieved by only a subset of patients. There remains a need for markers that connect clinical outcome with malignant-cell phenotypes and tissue-level immune organization. METHODS: We integrated The Cancer Genome Atlas HNSCC cohort (TCGA-HNSC), five Gene Expression Omnibus (GEO) validation cohorts, single-cell RNA sequencing, Visium spatial transcriptomics, cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq)-informed protein-potential inference, pharmacogenomic screening, genetic-risk analysis and experimental validation. A reconstructed 296-pipeline survival modelling framework was used to prioritize prognostic hub genes across validation-cohort-specific analyses. RESULTS: SIRPG was repeatedly ranked among the top ten selected genes in all five validation cohorts. At single-cell resolution, SIRPG-high tumor cells showed stronger malignant-cell features, immune-inhibitory and metabolic programs, Scissor-positive risk association, CLCA2/P53-related perturbation signals and inferred SIRPG-CD47/signal regulatory protein (SIRP) communication. Spatial analyses placed this axis within an immune-checkpoint-coupled niche, supported by Maxspin/multiview intercellular spatial modelling (MISTy) spatial coupling, communication analysis by optimal transport (COMMOT)-inferred CD47-SIRPG communication and scProTrans-inferred CD47/SIRPG protein-potential overlap. Functionally, SIRPG knockdown reduced HNSCC cell viability and increased apoptosis, whereas re-expression of short hairpin RNA (shRNA)-resistant SIRPG restored the CLCA2-BAX/BCL2 protein response. CONCLUSION: Together, these findings identify SIRPG as an immune-related prognostic hub and context-dependent tumor-cell regulator associated with apoptosis, immune communication and spatial microenvironmental organization in HNSCC.

Humans↗

PubMed2026

Tumor microenvironment-simulated organoids for personalized therapy prediction in head and neck squamous cell carcinoma.

Patient-derived organoids (PDOs) have emerged as promising models for predicting personalized drug responses in cancer therapy. However, the absence of essential immune and stromal components limits their ability to recapitulate the tumor microenvironment. Here, we established a total of 30 patient-derived organoids (PDOs) from 79 patients with locally advanced (LA) and recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). These PDOs maintained sustained expansion capacity and preserved the histopathological characteristics and genomic heterogeneity of their parental tumors. By integrating autologous immune cells and cancer-associated fibroblasts (CAFs) into PDOs, respectively, microenvironment-simulated PDOs (MS-PDOs) were established using a feasible co-culture condition. Compared with conventional PDOs, MS-PDOs-PBMC exhibited specific cytotoxicity and responses to PD-1/PD-L1 inhibitors, while MS-PDOs-CAFs showed enhanced tolerance to chemotherapy drugs, indicating that microenvironment components modulate therapeutic responses in HNSCC. The drug response profiles of MS-PDOs exhibited diverse sensitivity to PD-1/PD-L1 inhibitors, chemotherapy drugs, and combination regimens. Notably, the therapeutic predictions of MS-PDOs were consistent with clinical treatment outcomes, supporting their translational relevance. Collectively, MS-PDOs serve as a robust platform for modeling the tumor microenvironment and predicting therapeutic responses, supporting precision medicine-guided clinical decision-making and offering personalized treatment strategies for HNSCC patients.

Humans↗

PubMed2025

Analysis of genomic traits of oral and laryngeal cancer: A comparative study.

Oral and laryngeal cancers exhibit overlapping clinical features but distinct genomic profiles. In a study of 60 Head and neck squamous cell carcinomas(HNSCC) cases (30 OSCC, 30 LSCC), NGS revealed TP53 mutations in 70% of oral squamous cell carcinoma (OSCC) and 83% of laryngeal squamous cell carcinoma (LSCC). CDKN2A alterations were more common in OSCC (40%) than LSCC (20%), while PIK3CA mutations were higher in LSCC (30%). NOTCH1 mutations were more frequent in OSCC (27%) than LSCC (10%). Pathway analysis showed disruptions in p53 and PI3K-Akt, with stronger enrichment in LSCC (ES: 3.42). The results suggest site-specific tumor biology influencing therapeutic targets. Molecular profiling is crucial for precision treatment in head and neck cancers.

Oral cancer↗

PubMed2026

Accelerated Biological Aging Increases the Risk of Head and Neck Cancer: Insights From Genetic Instruments of Epigenetic Clocks.

Epigenetic clocks are robust biomarkers of biological aging and have been associated with cancer susceptibility. However, the relationship between genetically predicted epigenetic age acceleration and head and neck cancer risk remains unclear. Using a large case-control study of 2189 head and neck squamous cell carcinoma (HNSCC) cases and 2189 age- and sex-matched controls, we investigated the associations between polygenic scores (PGSs) for multiple epigenetic clocks and HNSCC risk, and evaluated their potential causal roles using two-sample Mendelian randomization (MR). Genome-wide association study (GWAS)-identified single nucleotide polymorphisms (SNPs) associated with four epigenetic clocks (HannumAge, HorvathAge, GrimAge, and PhenoAge) were used to construct clock-specific PGSs. Logistic regression models were applied to assess associations between PGSs and HNSCC risk, while MR analyses, including inverse-variance weighted (IVW), weighted median, and MR-Egger methods, were used to infer potential causal relationships. Among the 48 epigenetic clock-associated SNPs, 12 showed nominal associations with HNSCC risk, and one variant (rs2275558 in PBX1) remained significant after Bonferroni correction (OR = 0.67, 95% CI: 0.60-0.76). PGSs for all four epigenetic clocks were higher in cases than in controls. In logistic regression analyses, each standard deviation increase in HannumAge PGS was associated with a 25% higher risk of HNSCC (OR = 1.25, 95% CI: 1.10-1.41), whereas HorvathAge, GrimAge, and PhenoAge PGSs showed weaker positive associations (ORs ranging from 1.06 to 1.10). Individuals in the highest PGS quartile for all four epigenetic clocks exhibiting 14%-25% higher risk than those in the lower three quartiles. MR analyses supported potential causal effects of genetically predicted HannumAge (IVW OR = 1.24 per SD increase, 95% CI: 1.09-1.42) and GrimAge (IVW OR = 1.23 per SD increase, 95% CI: 0.98-1.56) on HNSCC risk, with consistent estimates in weighted median analyses. Our results highlight biological aging as a potential etiologic mechanism for HNSCC and suggest that epigenetic clock-related genetic profiles may improve HNSCC risk stratification.

Humans↗

PubMed2025

Identification of marginal zone B cells in head and neck cancer with immunomodulatory characteristics.

INTRODUCTION: Recently we observed high numbers of marginal zone B cells (MZBs) within murine head and neck squamous cell carcinoma (HNSCC) with immunosuppressive potential. To date, MZBs have not been linked to tumor development or tumor prevention. OBJECTIVES: Based on our previous findings the present study aimed to validate the presence of MZB in HNSCC and to investigate their possible implications in tumorigenesis and prognosis. METHODS: Flow cytometry was used to uncover MZB within tumors and blood of HNSCC patients. A single-cell RNA sequencing cohort of 118 HNSCC patients across different disease stages and 6 healthy donors (HDs) was compiled. Comparative transcriptomic profiling of B lymphocytes between HNSCC and HDs were performed. Downstream analysis, such as pathway enrichment, cell-cell communication, pseudotime trajectory inference, survival correlation, and spatial transcriptomics were applied. RESULTS: Two MZB subsets were revealed in tissues and blood of HNSCC patients and HDs. The tumor-associated MZBs were featured with hypoxia stress and viral-related hallmark genes. MZB-2, characterized by elevated expression of activation markers and immune-regulatory genes, displayed strong interactions with CD4+ T cells and antigen-presenting cells. These interactions were supported by costimulatory signals in HDs but were absent in HNSCC patients. Co-localization of MZB-2, germinal center B cell (GCB), and CD4+ follicular helper T cell (Tfh) was detected in HNSCC, suggesting the presence of an intratumoral MZB-Tfh-GCB axis. Clinically, MZB-2 abundance was associated with favorable prognosis in early-stage HNSCC, but not in advanced disease. Immunosuppressive gene signatures were not exclusive to MZBs, indicating that they do not represent a purely regulatory B cell phenotype. CONCLUSION: Our findings demonstrate an immunomodulatory role of MZBs in tumor immunity, balancing antigen presentation, cytokine signaling, and immune suppression. The association of MZB-2 with improved prognosis in early-stage HNSCC highlights its potential as a beneficial regulator of antitumor immunity during early tumor progression.

Humans↗

PubMed2025

Habitat radiomics predicts occult lymph node metastasis and uncovers immune microenvironment of head and neck cancer.

BACKGROUND: Occult lymph node metastasis (LNM) is a key prognostic factor for patients with head and neck squamous cell carcinoma (HNSCC). This study was to establish radiomics models derived from intratumoral, peritumoral, and habitat regions for identifying occult LNM in HNSCC. METHODS: Patients with pathologically confirmed HNSCC from three medical Centers (from March 2014 to April 2024) and The Cancer Genome Atlas (TCGA) were enrolled. Center 1 was split into training (n = 330) and internal test sets (n = 154), while Center 2 and Center 3 served as the external test set (n = 183). Genomic set (n = 50) from TCGA and single-cell RNA sequencing set (n = 6) from Center 1 were used for biological analysis. We used the intratumoral, peritumoral, and habitat volumes of interest (VOIs) to extract radiomics features, respectively. Based on Logistic Regression (LR), Support Vector Machine (SVM), and Random Forest (RF) classifiers, nine radiomics models were built to confirm the optimal predictive performance. The best-performing model, along with clinical-radiologic data, was combined to develop a hybrid model. The log-rank test was used to evaluate the model's prognostic performance. Additionally, bulk and single-cell RNA sequencing were applied for investigating the biological mechanisms underlying the optimal model. RESULTS: The RF-habitat radiomics model showed the best performance, achieving AUCs of 0.835-0.919 across all datasets. Survival analysis further confirmed the prognostic value of the RF-habitat radiomics model. The RF-habitat radiomics model and the hybrid model notably surpassed the clinical model in predictive performance. Moreover, the RF-habitat radiomics model was associated with the abundance level of exhaustion-associated CD8 + T cells, uncovering the immune microenvironment characteristics contributing to occult LNM in HNSCC. CONCLUSIONS: The RF-habitat radiomics model demonstrated excellent performance for predicting occult LNM in HNSCC across three cohorts, providing a non-invasive solution for occult LNM. Furthermore, radiogenomic analysis further revealed the biological associations of the model, primarily related to T cell dysfunction.

Humans↗

PubMed2025

Oral Lachnoanaerobaculum Levels and Survival in Patients With Head and Neck Cancer.

IMPORTANCE: The oral microbiome plays a critical role in cancer treatment responses, yet its influence on outcomes in patients with head and neck squamous cell carcinoma (HNSCC) undergoing (chemo)radiotherapy remains poorly understood. Identifying specific microbiome signatures associated with treatment effectiveness could provide novel prognostic biomarkers and therapeutic targets. OBJECTIVE: To investigate the association between salivary Lachnoanaerobaculum spp abundance and treatment outcomes in patients with HNSCC undergoing (chemo)radiotherapy and to explore potential mechanisms. DESIGN, SETTING, AND PARTICIPANTS: This prognostic study analyzed saliva samples from patients with HNSCC who were enrolled in 2 independent prospective biomarker studies (SALIVA and ZissTrans) and underwent definitive (chemo)radiotherapy. Oral microbiome composition was assessed using 16S rRNA gene sequencing. Tumor-infiltrating lymphocytes (TILs) were evaluated via immunohistochemistry in patients with available data. Findings were further assessed using data from The Cancer Microbiome Atlas and The Cancer Genome Atlas. Sample collection occurred from 2008 to 2011 (SALIVA) and from 2017 to 2022 (ZissTrans), and the data for this study were analyzed from July to December 2024. EXPOSURE: Definitive (chemo)radiotherapy. MAIN OUTCOMES AND MEASURES: The primary outcome was locoregional recurrence-free survival (LRFS) and a secondary outcome was overall survival (OS). Additional secondary analyses evaluated the association between Lachnoanaerobaculum spp levels and TIL levels, and the incidence of severe radiation-induced oral mucositis. RESULTS: The analysis included 92 patients with HNSCC (mean [SD] age, 61.1 [7.9] years; 15 female [16.3%] 77 male [83.7%] individuals) and found that higher Lachnoanaerobaculum spp abundance was associated with substantially improved LRFS (median, 69 vs 11 months; hazard ratio [HR], 0.50; 95% CI, 0.29-0.86) and OS (median, 75 vs 27 months; HR, 0.54; 95% CI, 0.30-0.98). This finding was confirmed by multivariable Cox regression (LRFS: HR, 0.50; 95% CI, 0.25-1.00; OS: HR, 0.37; 95% CI, 0.16-0.85). TILs were evaluated in 76 patients (82.2%) and showed that increased Lachnoanaerobaculum spp levels were associated with higher CD4-positive and CD8-positive TIL counts. Lachnoanaerobaculum spp abundance showed no meaningful association with severe radiation-induced oral mucositis. Data from The Cancer Microbiome Atlas (n = 157) indicated that higher intratumoral Lachnoanaerobaculum spp levels were associated with improved OS (HR, 0.62; 95% CI, 0.39-0.98). Transcriptomic analyses in The Cancer Genome Atlas cohort further supported an immune-stimulated tumor microenvironment in Lachnoanaerobaculum-high tumors. CONCLUSIONS AND RELEVANCE: This prognostic study found that higher salivary Lachnoanaerobaculum spp abundance was associated with improved tumor control and survival in patients with HNSCC undergoing (chemo)radiotherapy. These findings support further investigation into microbiome-targeted interventions to improve HNSCC treatment effectiveness.

Humans↗

PubMed2026

NOTCH1 acts as a tumor suppressor that induces early differentiation in head and neck cancer.

Inactivating NOTCH1 mutations in head and neck squamous cell carcinoma (HNSCC) were described over a decade ago, suggesting a tumor suppressor function - unlike its oncogenic role in other tumors. Today, much debate persists regarding a putative oncogenic role in HNSCC as well, with reports that NOTCH1 signaling drives tumor growth and a cancer stem cell (CSC) phenotype. In this work, comprehensive experiments unequivocally demonstrate that NOTCH1 is a tumor suppressor in HNSCC regardless of mutation or activation status and that it reduces CSC frequency. We developed a signature of NOTCH1 activation showing the pathway is associated with very early differentiation, an altered tumor microenvironment, and better prognosis. Clarifying whether NOTCH1 occasionally functions as an oncogenic driver in HNSCC is crucial to prognosis and personalized therapy. The results presented unify the field, reconcile conflicting data, and provide critical insights into the biological and clinical significance of NOTCH1, with broader implications in other squamous carcinomas with NOTCH1 mutations.

Receptor, Notch1↗

PubMed2026

Spatially defined microenvironmental niches are associated with clinical outcome and tumor ecosystem diversity in head and neck cancer.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) exhibits substantial biological heterogeneity that is not fully explained by human papillomavirus (HPV) status. The spatial organization of tumor, immune, and stromal cell populations and its relationship to clinical outcome remain incompletely understood. METHODS: We performed single-cell spatial transcriptomic and proteomic profiling of 44 primary HNSCC tumors, generating a spatial atlas of 19,471,501 cells across whole-slide tissue sections. Spatial niches and ecosystem states were identified through integrated computational analyses and evaluated for associations with tumor programs, clinicopathologic features, and patient outcomes. FINDINGS: HPV-negative tumors were enriched for fibroblast-rich, immune-poor niches associated with epithelial-mesenchymal transition and hypometabolic tumor programs, whereas HPV-positive tumors displayed more diverse immune, stromal, and vascular niche combinations and were enriched for immunogenic ecosystem states. Approximately 20% of HPV-positive tumors exhibited fibroblast-rich ecosystem architectures resembling HPV-negative disease and were associated with less favorable outcomes than other HPV-positive tumors of similar stage. In patient-derived co-culture models, extracellular matrix-associated fibroblasts were associated with epithelial-mesenchymal transition (EMT)-like tumor states, CD8+ T cell dysfunction, and chemotherapy resistance-associated phenotypes. CONCLUSIONS: Spatial ecosystem architecture is associated with clinically relevant heterogeneity beyond conventional HPV-based classification. Fibroblast-rich, immune-poor ecosystem states characterize a high-risk subset of HPV-positive tumors and may provide a framework for improved biological classification and risk stratification in HNSCC. FUNDING: This work was supported by the National Institutes of Health (R01CA291607 and R21CA267527-01) and the Feldstein Medical Foundation.

Humans↗

PubMed2026

Genetically Proxied Inhibition of Cholesterol-Lowering Drug Targets and Survival in HPV-Positive and Non-HPV-Driven Head and Neck Cancer: A Multicentre MR Study.

BACKGROUND: Cholesterol pathways may influence head and neck squamous cell carcinoma (HNSCC) progression, but evidence on prognosis is inconsistent. We used Mendelian randomization (MR) to test whether genetically proxied inhibition of major low-density lipoprotein cholesterol (LDL-C)-lowering drug targets and circulating lipid traits affects overall survival (OS) in HPV-positive and non-HPV-driven HNSCCs. METHODS: We proxied lifelong LDL-C lowering using 55 cis-acting single-nucleotide polymorphisms in HMGCR, NPC1L1, PCSK9, and LDL-receptor (LDLR) from the updated 2021 Global Lipids Genetics Consortium and instrumented circulating lipid traits. Two-sample MR estimated effects on OS in 4,869 multicentre HNSCC cases (1,291 HPV-positive; 3,578 non-HPV-driven) using minimally adjusted Cox models. Sensitivity analyses additionally adjusted for tumor stage and treatment, assessed collider bias using an external HNSCC incidence genome-wide association study, and examined between-center heterogeneity and colocalization. RESULTS: Using the updated Global Lipids Genetic Consortium 2021 instruments, genetically proxied HMGCR inhibition showed a directionally protective but nonsignificant association with OS in HPV-positive oropharyngeal HNSCC in the primary analysis [inverse variance weighted (IVW) HR = 0.19; 95% confidence interval (CI), 0.03-1.18; P = 0.08], with directionally concordant weighted median results. No corresponding protective association was observed for HMGCR in non-HPV-driven disease (IVW HR = 1.68; 95% CI, 0.78-3.63; P = 0.19). No clear evidence of association was observed for NPC1L1, PCSK9, LDLR, or circulating lipid traits in either HPV stratum. Colocalization did not support a shared causal variant. CONCLUSIONS: These analyses provide suggestive evidence that genetically proxied HMGCR inhibition may influence survival in HPV-positive oropharyngeal HNSCC. IMPACT: HMGCR-related pathways may be relevant to prognosis in HPV-positive oropharyngeal HNSCC, whereas clear survival effects of other cholesterol-lowering targets were not supported.

Humans↗

PubMed2026

HPV circulating tumor DNA as a potential prognostic and predictive biomarker in head and neck squamous cell carcinoma: a systematic review.

PURPOSE: Human papillomavirus circulating tumor DNA (HPVctDNA) has emerged as a promising prognostic biomarker in HPV-related head and neck squamous cell carcinoma (HNSCC). This systematic review aimed to synthesize current evidence on the diagnostic accuracy and prognostic value of HPVctDNA in HNSCC management. MATERIAL/METHODS: We systematically reviewed a PubMed-indexed database of studies published between January 2012 and September 2025. Eligible studies were assessed for design, primary tumor site and stage, treatment modality, HPVctDNA detection method, diagnostic accuracy (sensitivity and specificity), and reported clinical endpoints. Descriptive syntheses were performed; sensitivity and specificity were standardized to proportions and summarized as median values per group. RESULTS: A total of 60 studies, including 8,234 patients were analyzed, of which 41 (68.3%) focused exclusively on oropharyngeal squamous cell carcinoma (OPSCC) and 17 (28.3%) included mixed HPV-related HNSCC subsites and HPV-positive cancers of unknown primary. The median follow-up across the included studies was 23 months. Among the included studies, 19 were retrospective (31.7%) and 33 were prospective (55.0%), with a small proportion of cross-sectional and randomized clinical trials. Overall, 40 (66.7%) evaluated the role of HPVctDNA in a curative setting. Plasma was the most common sample type, analyzed in 55 studies (91.7%), while 5 studies also included saliva. Detection methods varied: 40 employed droplet digital PCR (ddPCR), 16 used quantitative PCR (qPCR) and 4 applied NGS-based assays. Most of these studies (38, 63.3%) evaluated the prognostic utility of HPVctDNA, while only 4 (6.7%) assessed HPVctDNA in a screening or diagnostic setting. Regarding diagnostic accuracy, the median sensitivity across evaluable studies was 91.1%, while the median specificity was 99.4%. In OPSCC-only cohorts, the median sensitivity and specificity were 89.4% and 99.4%, respectively. Dynamic changes in HPVctDNA levels during or after treatment were consistently associated with outcomes: clearance or sustained negativity correlated with higher response rates, improved progression-free survival and overall survival, while persistent positivity or increasing levels predicted disease progression and recurrence. CONCLUSIONS: HPVctDNA demonstrates high diagnostic and prognostic accuracy in HPV-related HNSCC, especially OPSCC, supporting its use for prognosis, treatment monitoring and early detection of recurrence. However, prospective interventional studies are still required to demonstrate that HPVctDNA-guided treatment decisions improve clinical outcomes before routine implementation.

Humans↗

PubMed2025

Epithelial competition determines gene therapy potential to suppress Fanconi Anemia oral cancer risk.

Fanconi Anemia (FA) is a heritable syndrome characterized by DNA damage repair deficits, frequent malformations and a significantly elevated risk of bone marrow failure, leukemia, and mucosal head and neck squamous cell carcinomas (HNSCC). Hematopoietic stem cell gene therapy can prevent marrow failure and lower leukemia risk, but mucosal gene therapy to lower HNSCC risk remains untested. Major knowledge gaps include an incomplete understanding of how rapidly gene-corrected cellular lineages could spread through the oral epithelium, and which delivery parameters are critical for ensuring efficient gene correction. To answer these questions, we extended an agent-based model of the oral epithelium to include the delivery of gene correction in situ to FA cells and determine the competitive dynamics between cellular lineages with and without gene correction. We found that only gene-corrected lineages with substantial proliferative advantages (probability of resisting displacement out of the basal layer [Formula: see text]) could spread on clinically relevant timelines, and that these lineages were initially at high risk of loss in the generations following correction. Delivering gene correction to many cells minimizes the risk of loss, while delivery to many distinct locations within a tissue maximizes the rate of spread. To determine the impact of mucosal gene therapy in preventing the clonal expansion of pre-cancerous mutations, we compared the expected burden of TP53 mutations in simulated tissue sections with and without gene correction. We found that when FA cells have elevated genome instability or a TP53-dependent proliferative advantage, gene correction can substantially reduce the accumulation of pro-tumorigenic mutations. This model illustrates the power of computational frameworks to identify critical determinants of therapeutic success to enable experimental optimization and support novel and effective gene therapy applications.

Fanconi Anemia↗