PURPOSE:Direct real-world comparisons between osimertinib and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are lacking, particularly regarding the comparative effectiveness, safety, and economic implications of different treatment sequencing strategies. METHODS:We emulated a target trial using the TriNetX database to study adults with newly diagnosed metastatic EGFR-mutant non-small cell lung cancer (NSCLC). After 1:1 propensity score matching, 777 patients in the first-line osimertinib arm were compared with 777 patients in the second-generation TKI arm. The primary outcome was overall survival (OS), with secondary outcomes including health care utilization and toxicity. RESULTS:First-line osimertinib demonstrated significantly longer median OS compared with second-generation TKIs (53.4 v 33.2 months; hazard ratio [HR], 0.618). Although sequential therapy (second-generation TKI followed by osimertinib) achieved similar OS, it was associated with significantly higher toxicity. Patients with brain metastases derived greater benefit from osimertinib (HR, 0.563). Osimertinib also significantly reduced rates of hospitalization, intensive care unit admission, and severe infections, generating substantial health care savings ($5.73 million per 1,000 patients) despite higher drug costs. CONCLUSION:First-line osimertinib provides prolonged OS and meaningful economic benefits over second-generation TKIs. Given the higher toxicity burden of sequential therapy despite similar survival outcomes, our findings support the implementation of first-line osimertinib to optimize patient experience and reduce health care utilization in metastatic EGFR-mutant NSCLC.

BACKGROUND:Understanding the mechanisms underlying drug resistance in head and neck squamous cell carcinoma (HNSCC) is critical for the development of effective therapeutic strategies. M2-type tumor-associated macrophages (M2-TAMs), activated by colony-stimulating factor 1 (CSF1), play a pivotal role in promoting chemoresistance and metastasis through immunosuppressive signaling and tumor-immune crosstalk. However, the precise mechanisms of CSF1-driven tumor support and macrophage activation remain incompletely understood. METHODS:We employed humanized patient-derived xenograft (PDX) models of drug-resistant HNSCC to examine the functional roles of CSF1 and its downstream effectors. Drug-tolerant persister (DTP) cells derived from these models were subjected to transcriptomic profiling. In vitro, both direct and indirect co-culture systems were used to assess the impact of CSF1 modulation on tumor cell viability and M2 macrophage activity. The therapeutic potential of the CSF1R inhibitor pexidartinib (PLX3397), alone and in combination with cisplatin, was evaluated in vivo. RESULTS:Our findings revealed that CSF1 silencing in M2 macrophages reduced the viability of cisplatin-resistant SCC9-P and HSC3-P cells in an indirect co-culture system, indicating a paracrine survival signal. In contrast, CSF1 overexpression enhanced tumor cell proliferation. In direct co-culture, CSF1 silencing inhibited M2 macrophage activation, whereas CSF1 overexpression promoted M2 proliferation and immunosuppressive activity. In vivo, pexidartinib effectively disrupted CSF1-mediated resistance and reduced the expression of key tumor-promoting factors, including DKK1, IL10, CXCL12, and AKT1. Clinically, high DKK1 and CSF1 expression correlated with cisplatin resistance and poor prognosis. CONCLUSION:This study underscores the dual role of CSF1 in regulating both tumor survival and M2 macrophage activation in HNSCC. Targeting the DKK1/CSF1 axis may represent a promising strategy to overcome chemoresistance by disrupting tumor-macrophage crosstalk and reprogramming the immunosuppressive microenvironment.

Background: The optimal sequencing of regorafenib and trifluridine/tipiracil (FTD/TPI) in refractory metastatic colorectal cancer (mCRC) remains uncertain, particularly in Asian populations. Methods: We retrospectively analyzed 110 patients with mCRC who sequentially received both agents between 2011 and 2025. Patients were categorized into regorafenib followed by FTD/TPI (Rego → FTD/TPI, n = 88) and FTD/TPI followed by regorafenib (FTD/TPI → Rego, n = 22). Co-primary endpoints were time to treatment discontinuation (TTD) and overall survival (OS). Propensity score-based weighting methods, including stabilized inverse probability of treatment weighting (primary analysis), were used to adjust for baseline imbalances. Multivariable Cox regression was performed as a sensitivity analysis. Results: No statistically significant differences were observed between treatment sequences. In the primary analysis, the hazard ratio (HR) for TTD was 1.01 (95% CI 0.71–1.43), and for OS was 1.19 (95% CI 0.67–2.12), with FTD/TPI → Rego as reference. Median TTD was 6.8 versus 8.9 months, and median OS was 14.6 versus 20.2 months, respectively. Conclusions: Clinical outcomes were comparable regardless of treatment order, supporting individualized sequencing decisions in refractory mCRC.

Breakthrough cancer pain (BTP) is a common and debilitating condition affecting most patients with advanced malignancy. While multiple rapid-onset opioid formulations are available, a lack of comprehensive comparative evidence has hindered evidence-based treatment selection. We conducted a network meta-analysis (NMA) to evaluate the relative efficacy of all available formulations and characterize their temporal analgesic profiles for BTP management. We performed a systematic search of PubMed, Embase, and the Cochrane Library for randomized controlled trials (RCTs) evaluating rapid-onset fentanyl formulations (intranasal fentanyl spray [INFS], fentanyl buccal tablet [FBT], fentanyl pectin nasal spray [FPNS], fentanyl sublingual tablet [FST], fentanyl buccal soluble film [FBSF], and oral transmucosal fentanyl citrate [OTFC]) and morphine preparations (oral morphine sulfate immediate release [MSIR] and subcutaneous morphine [SCM]) for BTP in adults. The primary outcome was the standardized mean difference (SMD) in pain intensity difference (PID) at 10, 15, 30, and 60 min post-administration. A frequentist random-effects NMA was conducted for each time point, and treatments were ranked using P-scores, a frequentist metric ranging from 0 to 1 that reflects the probability of a treatment being superior to competitors (higher values indicate better ranking; distinct from p-values for statistical significance). Seventeen RCTs involving 1,463 patients were included. Intranasal fentanyl spray (INFS) was consistently the most effective treatment across all time points, demonstrating statistically significant pain relief within 10 min (SMD: 0.85; 95

Background: Palliative care (PC) improves quality of life for patients with life-threatening illnesses. Despite global efforts, PC access remains limited. This study evaluated the 10-year trends of PC coverage and its impact on survival among advanced cancer patients at a tertiary medical center in Taiwan. Materials and Methods: A retrospective cohort study was conducted on 6096 hospitalized Stage IV cancer patients who died or were critically discharged between 2010 and 2020. Patients were categorized into PC and non-PC groups. Survival outcomes were analyzed using Kaplan–Meier curves and log-rank tests. Results: Of the cohort, 2792 patients received PC, and 3304 did not. PC recipients were older and had more comorbidities. The PC coverage rate increased annually over the decade. Patients receiving PC showed significantly better overall survival compared to those without PC, particularly in colon, esophageal, liver, lung, oral, prostate, and upper gastrointestinal cancers (P < 0.05). Conclusion: PC integration steadily improved over 10 years and was associated with survival benefits in several cancer types. These findings support early PC incorporation into oncology practice, though heterogeneity across malignancies warrants further investigation.

Background: Tegafur–uracil (UFT), an oral fluoropyrimidine developed in Asia, has been investigated as a maintenance or adjuvant therapy in various malignancies. Its use in head and neck cancers, however, remains limited to small retrospective studies, primarily from East Asia. Given the need for cost-effective maintenance strategies in resource-limited settings, we conducted an exploratory systematic review to evaluate the clinical utility of UFT in non-metastatic head and neck squamous cell carcinoma (HNSCC) and nasopharyngeal carcinoma (NPC). Methods: We systematically searched PubMed, EMBASE, and Cochrane Library from inception through 1 May 2025 for retrospective cohort studies evaluating UFT after definitive therapy in non-metastatic HNSCC or NPC. Study selection followed PRISMA guidelines. Given the heterogeneity of included studies, we performed a structured narrative synthesis using the SWiM (Synthesis Without Meta-analysis) framework to summarize survival outcomes, treatment settings, and clinical contexts. Results: Seven retrospective studies (four HNSCC, three NPC) involving 508 patients were included. UFT was generally administered at 300–400 mg/day for 6–12 months. Across studies, UFT use was associated with favorable disease-free and overall survival trends in high-risk subgroups, including patients with extranodal extension and persistent EBV DNA. Treatment adherence and toxicity profiles were acceptable. Conclusions: While the evidence remains limited and heterogeneous, this review highlights recurring signals of benefit associated with UFT maintenance therapy in selected high-risk patients. Prospective trials are warranted to confirm these findings and better define a possible role of UFT in maintenance therapy in some advanced non-metastatic HNSCC and NPC.

e18009 Background: This study addresses the need for alternative treatments in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients who are unsuitable for infusional 5-FU. Tegafur-Uracil, a substitute for 5-fluorouracil, was evaluated in combination with cisplatin and pembrolizumab as a first-line therapy. Conducted across five oncology centers in Taiwan, the retrospective study included 48 patients treated between January 2021 and December 2022. Methods: The endpoints were progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). Results: The median PFS was 15.1 months, and the median OS was 24.5 months. The ORR was 70%, with complete remission (CR) in 6% of patients and partial remission (PR) in 64%. Stable disease (SD) was observed in 13% of patients. Survival outcomes were significantly better for patients achieving an objective response (CR or PR) compared to those with SD or progressive disease (PD). The median OS varied: it was not reached for CR patients, 48.0 months for PR, 17.3 months for SD, and 6.0 months for PD. Conclusions: The findings suggest that Tegafur-Uracil combined with cisplatin and pembrolizumab offers a viable alternative for patients with poor baseline conditions, with an improved safety profile. Prospective studies are recommended to validate these results.

Background/purpose Malignant head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer with complex tumor microenvironment interactions. We aimed to identify key molecular drivers and therapeutic targets using bioinformatics approaches and examine their associations with cancer-associated fibroblasts (CAF). Materials and methods We analyzed three HNSCC transcriptomic datasets using bioinformatics. Protein–protein interaction networks were created using STRING, and pathway enrichment was also performed. The clinical relevance and CAF association of genes were evaluated using the TCGA HNSCC cohort and TIMER 2.0. Molecular docking predicted ovatodiolide binding to target proteins. Bioinformatics findings were validated in HNSCC cell lines and normal fibroblasts (WS1) by assessing cell viability, tumor spheroid formation, and CAF transformation through viability assays, qPCR, and Western blot. A mouse model of cisplatin resistance was used to test ovatodiolide's therapeutic effect. Results Our bioinformatics identified a nine-gene oncogenic network in HNSCC enriched in inflammatory and profibrotic pathways. A core three-gene SIS oncogenic signature (SERPINE1, INHBA, SPP1) was identified. High SIS expression correlated with poor survival and increased CAF infiltration. Docking predicted favorable binding of ovatodiolide to SERPINE1, SPP1, and INHBA. CAF-conditioned medium enhanced the stemness and chemoresistance of HNSCC cells, promoting SIS signature and stemness markers. Ovatodiolide suppressed oncogenic properties and CAF activation, decreasing SIS and CAF markers. In a mouse model, ovatodiolide overcame cisplatin resistance by reducing the SIS signature. Conclusion The SIS signature contributes to HNSCC progression, stemness, and drug resistance by facilitating CAF generation. Ovatodiolide disrupts this signature and inhibits CAF transformation.

Nasopharyngeal carcinoma (NPC) remains a challenging malignancy with high rates of recurrence following definitive therapy. This meta-analysis aimed to evaluate the efficacy of tegafur-uracil (UFT) maintenance therapy in patients with non-metastatic NPC after curative treatment. A systematic literature search of PubMed, Embase, and the Cochrane Library was performed to identify eligible studies. Three retrospective cohort studies including a total of 558 patients were analyzed. Random-effects meta-analysis demonstrated that UFT maintenance therapy significantly improved both progression-free survival [hazard ratio (HR)=0.53, 95% confidence interval (CI)=0.35-0.81] and overall survival (HR=0.37, 95%CI=0.21-0.65) compared to observation alone. Sensitivity analyses confirmed the robustness of these findings. However, trial sequential analysis indicated that the cumulative evidence did not meet the a priori information size required for a conclusive result, highlighting the need for further high-quality studies. In summary, UFT maintenance therapy may represent a promising option to reduce recurrence and improve survival in non-metastatic NPC, particularly in settings where access to novel agents is limited, but additional prospective studies are needed to confirm its clinical benefit.

Background:Patients with non-metastatic head and neck squamous cell carcinoma (HNSCC) face high risks of recurrence after curative-intent treatment. Maintenance therapy aims to prolong disease control during this vulnerable period. Tegafur-uracil (UFT), an oral fluoropyrimidine with a favorable toxicity profile, has demonstrated efficacy in other solid tumors. This study systematically evaluated the survival benefits of UFT as a maintenance therapy in HNSCC. Methods:A systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, with the protocol registered on the Open Science Framework. PubMed, Embase, and CENTRAL were searched through May 2025. Eligible studies included adult patients with non-metastatic HNSCC who received UFT after curative treatment, with comparison to observation or standard care. Hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were pooled using random-effects models. Trial sequential analysis (TSA) was performed to assess the conclusiveness of the findings. Results:Six observational studies including 1,373 patients were analyzed. UFT maintenance therapy was associated with improved PFS (HR: 0.68; 95% confidence interval (CI): 0.56 - 0.81; P < 0.001) and OS (HR: 0.54; 95% CI: 0.42 - 0.71; P < 0.001) compared with observation. TSA suggested that the available evidence may be sufficient to support a potential benefit for PFS, while for OS, further studies are still needed to strengthen the conclusions. Sensitivity analyses showed broadly consistent results; however, most included studies carried a moderate to serious risk of bias due to their non-randomized designs, which warrants cautious interpretation. Conclusions:UFT maintenance therapy may be associated with improved survival outcomes in patients with non-metastatic HNSCC. Its oral formulation, relatively low toxicity, and potential cost-effectiveness suggest that it could represent a feasible treatment option. However, these observations currently indicate only a possible trend and should not be regarded as definitive conclusions. Further prospective randomized controlled trials are required to validate the efficacy of UFT maintenance therapy and to establish standardized protocols for patient selection and dosing.

Little was known regarding the maintenance role in patients with ESCC.This study evaluates the impact of Tegafur-Uracil (UFUR) maintenance on survival in patients with ESCC following definitive concurrent chemoradiotherapy (dCCRT). Patients with pathologically confirmed ESCC and treated with dCCRT were analyzed retrospectively. Patients were stratified into UFUR (+) and UFUR (-) groups based on maintenance or not after dCCRT. Oncologic outcomes, including progression-free survival (PFS), overall survival (OS), locoregional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS), were compared between the groups. Multivariate Cox regression analysis was performed to identify independent predictors of survival. A total of 198 ESCC patients were included into our study. UFUR maintenance significantly reduced the overall recurrence rate (55% vs. 74%, p = 0.009), primarily driven by a reduction in distant metastases (44% vs. 63%, p < 0.001). The UFUR (+) group demonstrated markedly improved median OS (37.3 vs. 18.6 months, p = 0.002) and PFS (28.3 vs. 15.2 months, p = 0.014). Superior LRFS and DMFS were observed in the UFUR (+) group than those in UFUR (-) group, accounting for 29.6 vs. 13.4 months (p = 0.002) and 33.3 vs. 19.0 months (p = 0.010), respectively. Subgroup analyses revealed that UFUR(+) provided consistent benefits across all stages and all dCCRT responses. Multivariate analysis identified UFUR maintenance as an independent predictor of survival, alongside tumor stage and response to dCCRT. UFUR maintenance significantly improves outcomes in patients with ESCC following dCCRT, which might be considered as part of personalized treatment strategies to optimize prognosis in ESCC.

Head and neck squamous cell carcinoma (HNSCC) presents significant therapeutic challenges, particularly in patients with advanced disease. Despite advancements in treatment, high recurrence rates and poor overall survival (OS) remain major concerns. This study evaluates the impact of tegafur-uracil (UFUR) maintenance therapy on survival outcomes in patients with advanced HNSCC following definitive chemoradiotherapy. A cohort of 424 advanced HNSCC patients treated with definitive chemoradiotherapy were analyzed, with a median follow-up of 25 months. Patients were stratified into UFUR (+) and UFUR (-) groups, with baseline characteristics balanced across both arms. Oncologic outcomes, including recurrence-free survival (RFS), OS, locoregional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were compared between these groups. UFUR maintenance therapy significantly reduced recurrence rates (34

PURPOSE:To evaluate the efficacy and safety of nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil (5-FU) and leucovorin (LV) in patients with platinum-refractory or intolerant head and neck squamous cell carcinoma (HNSCC) and esophageal squamous cell carcinoma (ESCC). METHODS:In this multicenter, phase 2 study (NCT03712397), patients with advanced HNSCC (n = 43) or ESCC (n = 16) who had failed or were intolerant to platinum-based chemotherapy received biweekly nal-IRI 80 mg/m2 (equivalent to 70 mg/m2 of irinotecan base), LV 400 mg/m2, and 5-FU 2400 mg/m2 until progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR). RESULTS:In the intent-to-treat analysis, the ORR and disease control rate were 8.5% and 59.3% for the entire group. In the HNSCC subgroup, ORR and disease control rate were 11.6% and 65.1%, with a median progression-free survival (PFS) of 2.7 months and an overall survival (OS) of 8.1 months. By contrast, no objective responses were observed in ESCC (ORR 0%, disease control rate 43.8%, median OS 4.2 months). The most common grade 3/4 toxicities were lymphopenia (50.8%), neutropenia (42.4%), leukopenia (33.9%), anemia (28.8%), and anorexia (8.5%). CONCLUSIONS:Nal-IRI/5-FU/LV demonstrates modest activity with acceptable safety profiles in patients with platinum-refractory or intolerable advanced HNSCC. The exploratory findings warrant confirmation in larger, randomized studies. TRIAL REGISTRATION:ClinicalTrials.gov: NCT03712397.

Background: The benefit of adjuvant chemotherapy for low-risk, mismatch repair proficient (pMMR) stage IIA colon cancer is uncertain. Surveillance is standard, but some patients relapse. Tegafur-uracil (UFT) is a low-toxicity oral option that may offer benefit; Methods: This retrospective study included patients with resected low-risk, pMMR stage IIA colon cancer (2013–2022). Patients receiving ≥5 postoperative UFT prescriptions were compared with those under surveillance. Propensity score matching (1:1) was applied, and disease-free survival (DFS) and overall survival (OS) were analyzed using Kaplan–Meier and Cox models with sensitivity analyses.; Results: Among 279 eligible patients, 71 matched pairs were analyzed. UFT reduced the risk of recurrence or death by 57% (DFS HR = 0.43, 95% CI 0.25–0.75, p = 0.002) and mortality by 62% (OS HR = 0.38, 95% CI 0.21–0.68, p < 0.001); Conclusions: UFT improved DFS and OS in low-risk pMMR stage IIA colon cancer, suggesting surveillance alone may undertreat some patients. Prospective trials are warranted.

Head and neck squamous cell carcinoma (HNSCC) faces low response rates to anti-PD-1 immunotherapies, highlighting the need for enhanced treatment strategies. Auranofin, which inhibits thioredoxin reductase (TrxR) through its gold-based composition, has shown potential in cancer treatment. It targets the TrxR system, essential for safeguarding cells from oxidative stress. The overproduction of TrxR in cancerous cells supports their proliferation. However, auranofin's interference with this system can upset the cellular redox equilibrium, boost levels of reactive oxygen species, and trigger the death of cancer cells. This study is the first to highlight TXNRD1 as a crucial factor contributing to resistance to anti-PD-1 treatment in HNSCC. In this study, we identified targetable regulators of resistance to immunotherapy-induced ferroptosis in HNSCC. We observed a link of thioredoxin reductase 1 (TXNRD1) with tumoral PD-L1 expression and ferroptosis suppression in HNSCC. Moreover, HNSCC tumors with aberrant TXNRD1 expression exhibited a lack of PD-1 response, NRF2 overexpression, and PD-L1 upregulation. TXNRD1 inhibition promoted ferroptosis in HNSCC cells with NRF2 activation and in organoid tumors derived from patients lacking a PD-1 response. Mechanistically, TXNRD1 regulated PD-L1 transcription and maintained the redox balance by binding to ribonucleotide reductase regulatory subunit M2 (RRM2). TXNRD1 expression disruption sensitized HNSCC cells to anti-PD-1-mediated Jurkat T-cell activation, promoting tumor killing through ferroptosis. Moreover, TXNRD1 inhibition through auranofin cotreatment synergized with anti-PD-1 therapy to potentiate immunotherapy-mediated ferroptosis by mediating CD8+ T-cell infiltration and downregulating PD-L1 expression. Our findings indicate that targeting TXNRD1 is a promising therapeutic strategy for improving immunotherapy outcomes in patients with HNSCC.

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive cancer affecting over half a million people worldwide each year. Although recent FDA-approved treatments, like cetuximab, have shown promise, the five-year survival rate remains below 50 %. This underscores the need to identify molecular signatures predicting clinical outcomes and potential therapeutic targets. Notably, the alteration of tyrosine-protein kinase Met (c-Met), a hepatocyte growth factor (HGF) receptor, stimulates tumor growth and metastasis across various cancers. However, its role and clinical implications in HNSCC remain unexplored. In HNSCC, MET's downstream signaling, mediated by phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), is activated by fibronectin 1 (FN1), an extracellular matrix protein, fostering cancer progression. Additionally, FN1 and transforming growth factor-β (TGFB) are known to induce epithelial-mesenchymal transition in numerous cancers, leading to metastasis. Our computational analysis revealed significant upregulation of MET/FN1/TGFBI in HNSC at the mRNA level compared to normal samples. Given the immune system's pivotal role in HNSC progression, we analyzed the association of our target genes with immune infiltration. Our findings suggest a correlation between MET/FN1/TGFBI oncogenes and various stromal cells, highlighting their potential role in cancer recurrence and therapeutic resistance. We further explored the therapeutic potential of sulfasalazine, an anti-inflammatory drug. Molecular docking experiments revealed that sulfasalazine had a strong affinity for MET, FN1, and TGFBI, outperforming standard inhibitors in binding energy. These observations suggest sulfasalazine could be a promising MET/FN1/TGFBI gene signature inhibitor. Our study offers preclinical evidence supporting sulfasalazine as a standalone therapeutic agent and an adjunct to counteract cisplatin resistance in HNSC cells.

Background and Objectives: Postoperative adjuvant therapy with uracil and tegafur (UFT) is often used for stage II colon cancer in Japan, but a limited number of studies have investigated the effects of UFT in these patients. Materials and Methods: We conducted a population-based cohort study in patients with resected stage II colon cancer comparing the outcomes after postoperative adjuvant chemotherapy with UFT with an observation-only group. The data were collected from the Taiwan National Health Insurance Research Database from 2000 to 2015. The outcomes of the study were disease-free survival (DFS) and overall survival (OS). The hazard ratios (HRs) were calculated using multivariate Cox proportional hazard regression models. Results: No differences in the DFS and OS were detected between the UFT (1137 patients) and observation (2779 patients) cohorts (DFS: adjusted HR 0.702; 95% confidence interval (CI) 0.489–1.024; p = 0.074) (OS: adjusted HR 0.894; 95% CI 0.542–1.186; p = 0.477). In the subgroup analyses of the different substages, UFT prolonged DFS in patients with stage IIA colon cancer (adjusted HR 0.652; 95% CI 0.352–0.951; p = 0.001) compared with DFS in the observation cohort, but no differences in the OS were detected (adjusted HR 0.734; 95% CI 0.475–1.093; p = 0.503). Conclusions: Our results show that DFS improved significantly in patients with stage IIA colon cancer receiving UFT as a postoperative adjuvant chemotherapy compared with DFS in the observation group.

Head and neck squamous cell carcinomas (HNSCC) are prevalent malignancies with a disappointing prognosis, necessitating the search for theranostic biomarkers for better management. Based on a meta-analysis of transcriptomic data containing ten clinical datasets of HNSCC and matched nonmalignant samples, we identified SERPINE1/MMP3/COL1A1/SPP1 as essential hub genes as the potential theranostic biomarkers. Our analysis suggests these hub genes are associated with the extracellular matrix, peptidoglycans, cell migration, wound-healing processes, complement and coagulation cascades, and the AGE-RAGE signaling pathway within the tumor microenvironment. Also, these hub genes were associated with tumor-immune infiltrating cells and immunosuppressive phenotypes of HNSCC. Further investigation of The Cancer Genome Atlas (TCGA) cohorts revealed that these hub genes were associated with staging, metastasis, and poor survival in HNSCC patients. Molecular docking simulations were performed to evaluate binding activities between the hub genes and antrocinol, a novel small-molecule derivative of an anticancer phytochemical antrocin previously discovered by our group. Antrocinol showed high affinities to MMP3 and COL1A1. Notably, antrocinol presented satisfactory drug-like and ADMET properties for therapeutic applications. These results hinted at the potential of antrocinol as an anti-HNSCC candidate via targeting MMP3 and COL1A1. In conclusion, we identified hub genes: SERPINE1/MMP3/COL1A1/SPP1 as potential diagnostic biomarkers and antrocinol as a potential new drug for HNSCC.