Search Results (216)

This study aimed to investigate the selective anticancer activity of the curcumin analog PAC (3,5-Bis-4-hydroxy-3-methoxybenzylidene)-N-methyl-4-piperidone). Normal gingival epithelial cells (GECs), cancerous gingival cells (Ca9-22) and tongue squamous carcinoma cells (CAL27) were exposed to increasing concentrations of PAC (0–10 µM) for 24 h. Cell viability and cytotoxicity were evaluated using MTT and LDH assays, while apoptosis and caspase activation were analyzed by Annexin V/PI staining and flow cytometry. Gene-expression profiling was performed using RT² Profiler PCR arrays. PAC significantly inhibited Ca9-22 and CAL27 cell proliferation in a concentration-dependent manner, with an IC₅₀ value of 5 µM, while exerting no noticeable cytotoxic effects on normal GEC. PAC treatment induced significant early and late apoptosis associated with increased caspase activity in both oral cancer cell lines. Transcriptomic analyses revealed extensive modulation of apoptosis-related genes. In Ca9-22 cells, PAC predominantly suppressed anti-apoptotic and survival-associated genes, including BCL2, BIRC3, BIRC5, XIAP, CFLAR, and NFKB1. In contrast, CAL27 cells exhibited a more pronounced pro-apoptotic transcriptional profile characterized by upregulation of TP53, APAF1, CASP1, BID, and TNF. Gene interaction network analyses further demonstrated that PAC targets highly interconnected apoptotic signaling pathways. Collectively, these findings demonstrate that PAC exerts potent selective anticancer activity against OSCC cells through modulation of intrinsic and extrinsic apoptotic pathways. These results further support the therapeutic potential of PAC as a promising multitarget candidate for oral cancer treatment. Full article

Background/Objectives: Oral tongue squamous cell carcinoma (OTSCC) remains clinically challenging because conventional clinicopathological markers do not fully explain variability in recurrence and survival. This systematic review and functional meta-synthesis aimed to identify and critically appraise studies using preoperative magnetic resonance imaging (MRI)-based radiomics, artificial intelligence (AI), deep learning, or quantitative MRI-derived models to predict recurrence and prognostic outcomes in OTSCC. Methods: PubMed, Scopus, and Embase were searched from inception to March 2026. Eligible studies included prognostic model investigations in adults with OTSCC or primary tongue cancer without reported base-of-tongue/oropharyngeal involvement, undergoing preoperative MRI and surgery, with recurrence- or survival-related follow-up. The primary synthesis was a functional meta-synthesis; pooling was not performed because studies were not sufficiently comparable. Results: Seven retrospective studies were included, with a summed descriptive sample of 1287 participants. The evidence base was heterogeneous in MRI sequences, segmentation workflows, model architecture, validation strategy, and endpoint definition. Functional meta-synthesis identified four domains: direct recurrence-oriented modeling, broader prognostic stratification, reported incremental or complementary value over clinical frameworks, and translational maturity/technical implementation. Several studies reported associations between MRI-derived signatures and recurrence- or survival-related outcomes, but findings were interpreted narratively because of differences in primary endpoints, imaging features, model design, validation methods, and outcome definitions. Most studies were judged at high overall risk of bias, and certainty of evidence ranged from low to very low. Conclusions: MRI-based radiomics and AI show preliminary promise for prognostic stratification in OTSCC, particularly recurrence-related risk refinement, but current evidence remains limited by retrospective design, heterogeneity, sparse external validation, and low certainty. Full article

Background: Late-stage presentation of oral cancer remains a major challenge in low- and middle-income countries and contributes substantially to poor clinical outcomes. Data describing oral cancer presentation patterns in Indonesia remain limited. This study aimed to characterize the clinicopathological profile, stage distribution, treatment patterns, and exposure-related characteristics of oral cancer patients treated at a national referral center in Indonesia. Methods: A retrospective study was conducted using medical records of 404 patients with histopathologically confirmed oral malignancies treated between 2021 and 2025. Descriptive analyses were performed to summarize demographic, clinicopathological, staging, treatment-related, and exposure-related characteristics. Results: The mean age at diagnosis was 49.17 ± 14.11 years, with a relatively balanced sex distribution. The tongue was the most common primary tumor site (76.0%), and oral squamous cell carcinoma (OSCC) represented the predominant histopathological diagnosis (81.9%). Late-stage presentation (stage III–IV) was observed in 64.1% of all cases and increased to 70.7% among patients with available staging information, while 29.2% of patients had incomplete or undefined staging data. Surgical treatment, either alone or combined with adjuvant therapies, was the most frequently employed treatment modality. Notably, 21.5% of patients had no documented definitive oncologic treatment during the recorded treatment period. Smoking was reported by 35.4% of patients, alcohol consumption by 4.0%, and a family history of cancer by 24.8%. Conclusions: Advanced-stage oral cancer was highly prevalent in this referral-based cohort. The substantial burden of late-stage disease, together with incomplete staging information and the proportion of patients without documented definitive treatment, highlights challenges related to staging completeness, treatment documentation, and cancer care monitoring. These findings support efforts to strengthen early detection, referral coordination, and cancer care monitoring within the Indonesian healthcare system. Full article

Background/Objectives: Behçet’s disease is a chronic relapsing multisystem inflammatory disorder characterized by recurrent mucocutaneous ulceration, vasculitis, and exaggerated inflammatory responses to minor trauma. These features may adversely affect wound healing after major head and neck oncologic reconstruction. This case report describes repeated wound breakdown after oral cavity reconstruction in a patient with Behçet’s disease and advanced floor-of-mouth squamous cell carcinoma. Methods: A 51-year-old woman with Behçet’s disease and T4N2bM0 squamous cell carcinoma involving the floor of the mouth and tongue underwent tumor resection followed by reconstruction of the oral cavity defect using a right anterolateral thigh perforator free flap. Subsequent surgical procedures included debridement of necrotic tissue, negative-pressure wound therapy, split-thickness skin grafting of the thigh donor site, and salvage tumor resection with pectoralis major myocutaneous flap reconstruction after tumor recurrence. Results: After the initial anterolateral thigh free flap reconstruction, flap perfusion was satisfactory in the immediate postoperative period; however, delayed marginal necrosis developed from the distal tongue-side flap margin, whereas the floor-of-mouth portion remained relatively stable. The right thigh donor site also developed progressive suture-line necrosis and wound dehiscence, requiring operative debridement, negative-pressure wound therapy, and split-thickness skin grafting. Although skin grafting achieved eventual donor-site coverage, partial graft necrosis and delayed secondary healing occurred. Persistent fistula and wound instability delayed postoperative radiotherapy, and recurrent floor-of-mouth squamous cell carcinoma subsequently developed approximately 6 months after the initial surgery. After salvage resection and pectoralis major myocutaneous flap reconstruction, the flap appeared viable at inset, but marginal ecchymosis, partial necrosis, and wound dehiscence again developed, requiring additional debridement, quilting sutures, and negative-pressure wound therapy. The wound gradually stabilized with staged wound management. Conclusions: This case illustrates a multifactorial pattern of repeated marginal wound breakdown after technically successful flap reconstruction in a patient with Behçet’s disease. Behçet-related pathergy-like inflammation, vasculitis, and microcirculatory dysfunction may represent possible contributing mechanisms, but they were not directly proven in this patient. In oral cavity reconstruction, such wound instability may delay adjuvant therapy and adversely affect oncologic outcomes. Careful perioperative planning, close multidisciplinary coordination, meticulous tension-free closure, early recognition of wound compromise, and readiness for staged wound management are essential in patients with Behçet’s disease undergoing major head and neck oncologic reconstruction. Full article

Background and Clinical Significance: Localized amyloidoma rarely affects the tongue base, a site far less commonly involved than the larynx. When it does occur at this location, the clinical and radiological presentation can closely mimic oropharyngeal malignancy, making it a genuine diagnostic pitfall for head and neck surgeons. Establishing the diagnosis demands histological proof, and ruling out systemic amyloidosis is an essential prerequisite. Case Presentation: An 80-year-old nonsmoking woman was evaluated for progressive dysphagia and globus sensation that had worsened over several years. Endoscopy revealed a firm, lobulated mass at the tongue base, centered on the glossotonsillar sulcus. Incisional biopsy under local anesthesia showed amyloid deposits. MRI demonstrated an avidly enhancing, well-circumscribed lesion without invasion of the deep neck spaces. A comprehensive systemic evaluation—including serum and urine protein electrophoresis with immunofixation, serum free light chains (κ/λ ratio 1.05), echocardiography, and bone marrow biopsy—yielded no evidence of systemic AL amyloidosis or plasma-cell dyscrasia. The mass was excised through transoral robotic surgery (TORS). Histopathology confirmed Congo red-positive, apple-green birefringent amyloid with lambda light-chain restriction; staining for AA amyloid and transthyretin was negative. The patient was diagnosed with primary localized lingual amyloidoma of the AL lambda type and remained symptom-free, with no endoscopic evidence of recurrence, at 12-month follow-up. Discussion: Amyloidoma deserves a place in the differential diagnosis of tongue base masses, particularly when the clinical picture does not fit squamous cell carcinoma. Congo red staining under polarized light, immunohistochemical light-chain typing, and a rigorous systemic workup are the cornerstones of diagnosis. Robotic-assisted transoral excision provides excellent access to the tongue base with low morbidity. Conclusions: This case underscores the need to consider amyloidoma when evaluating tongue base lesions, the central role of Congo red staining and light-chain typing, and the utility of TORS as an effective treatment option for selected symptomatic cases. Full article

Background/Objectives: This study aimed to explore the potential value of narrow-band-imaging (NBI)-derived mean optical intensity (MOI) in monitoring the progression of oral squamous cell carcinoma (OSCC), from the normal oral mucosa through epithelial dysplasia to invasive carcinoma. We compared differences in the NBI MOI among distinct pathological stages, so as to provide preliminary evidence for its clinical application in auxiliary diagnosis and progression assessment for OSCC. Methods: A total of 40 human oral mucosal specimens (15 normal, 15 oral leukoplakia, 10 OSCC) were enrolled for NBI image acquisition and MOI measurements. A 4-nitroquinoline-1-oxide (4NQO)-induced mouse OSCC model (n = 34) was used to dynamically record MOI changes across different pathological stages. A syngeneic tongue tumor mouse model (n = 16) was further established to evaluate whether MOI could reflect tumor formation and growth. All MOI values were quantified using ImageJ software with standardized region-of-interest (ROI) selection and background correction. Results: In clinical samples, MOI values decreased progressively from the normal mucosa (129.6 ± 5.991 arbitrary units (a.u.)) to oral leukoplakia (OLK) subgroups, including mild dysplasia (104.6 ± 3.757 a.u.) and moderate-to-severe dysplasia (91.77 ± 4.345 a.u.), and further to OSCC (54.41 ± 14.40 a.u.). In the 4NQO model, the MOI of the lingual mucosa was highest in the healthy control group (167.3 ± 10.05 a.u.) and gradually declined with increasing dysplasia severity, reaching the lowest level at the OSCC stage (48.67 ± 10.07 a.u.). In the syngeneic tumor model, the MOI was significantly lower in tumor-bearing mice than in healthy controls (47.85 ± 10.44 a.u. vs. 119.7 ± 14.20 a.u., p < 0.001). Receiver operating characteristic (ROC) analysis demonstrated good diagnostic performance of the MOI in distinguishing healthy tissue from cancerous lesions. Conclusions: NBI-derived MOI may quantitatively reflect the dynamic alterations of the oral mucosa during oral carcinogenesis and could represent a potential biomarker enabling the non-invasive, repeatable early evaluation and dynamic monitoring of OSCC. Full article

Background: Understanding lymph node involvement in head and neck cancers is crucial for developing effective treatment strategies and improving patient outcomes. Accurate identification of nodal metastases can enhance prognostic assessment, improve survival rates, and reduce the risk of recurrence. This study aimed to evaluate the association of lymph node metastases with primary tumor characteristics, with a particular focus on tumor stage and primary tumor location in head and neck squamous cell carcinoma (HNSCC). Methods: The study included 170 patients diagnosed with HNSCC at a single medical center between 2022 and 2025. Clinical and pathological assessments of the size and extent of primary tumors were performed according to the American Joint Committee on Cancer TNM classification, version 8. Results: The study cohort consisted of adult patients with a mean age of 61.9 years, of whom 40.6% were female. The tongue was the most common primary tumor site (54.7%), followed by the floor of the mouth (22.4%) and the jaw (8.8%). Clinical staging identified lymph node metastases (cN1 or higher) in 32.4% of patients, whereas pathological evaluation revealed nodal involvement in 38.9%. A statistically significant association was observed between tumor stage and the presence of lymph node metastases (p < 0.001). Additionally, the frequency of nodal metastases varied by anatomical site, with the highest rates observed in tumors of the floor of the mouth and the tongue. Conclusions: These findings suggest that both tumor stage and primary tumor location are associated with an increased risk of lymph node metastases. The results underscore the limitations of clinical staging in detecting nodal disease and highlight the prognostic significance of tumor stage and anatomical site in assessing metastatic risk. Full article

Oral squamous cell carcinoma (OSCC), comprising ~90% of oral malignancies, remains a major global health burden with rising incidence despite declining tobacco use. While tobacco and alcohol are classic dominant risk factors, a distinct subgroup of nonsmoking, nondrinking (NSND) patients is increasingly recognized, accounting for 15–35% of OSCC cases in many cohorts, particularly in developed countries. This emerging epidemic shows striking demographic patterns: strong female predominance (often 65–77% of cases), bimodal age distribution with peaks in young adults (<45 years) and elderly individuals (>70 years), and overrepresentation among non-Hispanic White and certain Asian populations. Unlike traditional habit-related OSCC, which favors the floor of the mouth in older males, NSND tumors predominantly arise on the lateral tongue, gingiva, and buccal mucosa. Etiopathogenesis extends far beyond conventional carcinogens and involves multifactorial mechanisms, including chronic mechanical irritation from dental factors, oral microbiome dysbiosis enriched with periodontal pathogens (e.g., Fusobacterium nucleatum and Porphyromonas gingivalis), limited roles for viruses (minimal HPV contribution, possible EBV or “hit-and-run” HSV effects), genetic susceptibilities (e.g., Fanconi anemia and CDKN2A mutations), epigenetic changes, hormonal influences contributing to female bias, metabolic conditions (diabetes and hyperlipidemia), poor oral hygiene, and chronic inflammation. NSND OSCC frequently exhibits a distinct immunological profile with higher tumor-infiltrating lymphocytes and PD-L1 expression, potentially favoring immunotherapy, though prognosis remains heterogeneous—better in some cohorts due to fewer comorbidities, yet worse in young patients with higher recurrence and second primary tumor risks. Delayed diagnosis is common due to low suspicion in “low-risk” individuals. This review underscores NSND OSCC as a unique entity requiring expanded risk assessment, heightened clinical vigilance for persistent oral lesions regardless of habit history, and targeted research into novel prevention and therapeutic strategies. Full article

Background: Oral squamous cell carcinoma (OSCC) remains a clinically challenging malignancy characterized by aggressive behavior and limited therapeutic options. Bitter taste receptors (TAS2Rs), expressed across multiple tissues and cancer types, have recently emerged as regulators of tumor biology and immune responses; however, their functional significance in OSCC remains poorly understood. Methods: Immunohistochemical analysis was performed using surgically resected human tongue OSCC specimens and a tissue microarray (TMA) cohort. In parallel, four TAS2R agonists were evaluated in SCC7 cells to assess intracellular calcium responses. RNA sequencing was conducted to analyze transcriptional changes following diphenidol treatment, and functional assays, including proliferation, migration, and apoptosis analyses, were performed in vitro. Antitumor effects were further evaluated in a syngeneic SCC7 mouse model, followed by TUNEL staining and flow cytometry to assess apoptosis and immune cell infiltration. Results: TAS2R38 expression was markedly upregulated in dysplastic and invasive OSCC lesions with predominant nuclear localization and was associated with histological grade and clinical stage, indicating an early and sustained alteration during tumor progression. Among the agonists tested, diphenidol most strongly induced IP₃-dependent intracellular Ca²⁺ elevation. RNA sequencing revealed upregulation of Il1rl1 and Lzts2. Functionally, diphenidol significantly suppressed SCC7 cell proliferation and migration and induced apoptosis in vitro. In vivo, diphenidol reduced tumor volume and weight and increased apoptotic activity. Flow cytometry demonstrated a marked reduction in tumor-infiltrating CD4⁺CD25⁺Foxp3⁺ regulatory T cells, indicating modulation of the tumor immune microenvironment. Conclusions: TAS2R activation by diphenidol suppresses tumor growth through both tumor-intrinsic mechanisms and modulation of the tumor immune microenvironment in OSCC. These findings define TAS2R-mediated calcium signaling as a novel axis linking tumor progression and immunoregulation. Given that diphenidol is a clinically approved drug with an established safety profile, our results provide a strong rationale for TAS2R-targeted drug repurposing strategies in cancer therapy. Full article

Oral squamous cell carcinoma (OSCC) typically develops in individuals with established risk factors such as tobacco and alcohol use, yet an increasing number of cases occur in young non-smoking, non-drinking (NSND) patients. We report a case of oral tongue OSCC in a 33-year-old woman who is a never-smoker and never-drinker without identifiable environmental or local risk factors. The patient underwent surgical treatment followed by adjuvant radiotherapy and remains disease-free 15 months after therapy. Whole-exome sequencing (WES) revealed a pathogenic truncating TP53 mutation together with additional somatic alterations affecting genes involved in DNA repair, hypoxia adaptation, mitochondrial function, and epigenetic regulation. The heterogeneous mutational profile suggests branched tumor evolution and the involvement of non-classical tumorigenic pathways. This report contributes to the growing evidence that OSCC in young NSND patients represents a biologically distinct subgroup and demonstrates the value of comprehensive genomic profiling for improving understanding of tumor heterogeneity and potential molecular drivers in the absence of traditional carcinogenic exposures. Full article

Tongue squamous cell carcinoma (TSCC) is an aggressive malignancy with poor prognosis and limited therapeutic options. Herbal medicines with multitarget activities and low toxicity have attracted increasing attention in cancer adjuvant therapy. This study aimed to investigate the anti-tumor effects and underlying mechanisms of the water extract of Andrographis paniculata (APW) in TSCC in vitro and in vivo. Two TSCC cell lines, Cal-27 and SCC25, were used for cell-based functional and mechanistic studies, while a Cal-27 xenograft-bearing mouse model was established for evaluating the in vivo effect of APW treatment. Our results showed that APW could significantly inhibit the proliferation of Cal-27 and SCC25 cells and induce apoptosis in a concentration-dependent manner. APW could promote mitochondrial-mediated apoptosis by upregulating Bax and cleaved caspase proteins but downregulating Bcl-2 in TSCC cells. It also suppressed the Wnt/β-catenin signaling pathway, reducing β-catenin expression and its downstream targets, CCND1, MYC, and JUN. Furthermore, APW disrupted mitochondrial integrity, induced cytochrome c release, and reduced mitochondrial membrane potential. APW also inhibited epithelial–mesenchymal transition, increasing E-cadherin and decreasing N-cadherin and vimentin expressions, thereby suppressing cell migration of TSCC cells. Furthermore, the 5-week APW treatment significantly reduced tumor growth and angiogenesis without evident hepatic or renal toxicity in Cal-27 xenograft-bearing mice. In conclusion, APW exerted potent anti-tumor effects by targeting both the Wnt/β-catenin pathway and mitochondrial apoptotic machinery, suggesting the great potential of APW as an adjuvant therapeutic candidate for TSCC treatment. Full article

Tongue squamous cell carcinoma (TSCC) is clinically heterogeneous, and patients with a similar TNM stage can experience markedly different outcomes. We systematically reviewed omics-driven studies to identify prognostic TSCC biomarkers. Although fundamentally prognostic, we discussed their theoretical translational relevance regarding future clinical decisions—such as treatment stratification or surveillance intensity—while strictly framing them as preliminary, hypothesis-generating targets. PubMed, Scopus, Web of Science, and Cochrane were searched for original human studies published between 2014 and 2024 using high-throughput genomic or transcriptomic profiling. Study selection followed referred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), data were extracted with a structured workbook, and risk of bias was assessed using QUIPS and PROBAST, with reporting completeness appraised using REMARK. Seventeen studies were included, identifying 85 distinct biomarkers. Across biomarkers supported by multivariable overall survival analyses, higher-risk associations were reported for NELL2, PDE4D, CTTN, HBEGF, and CA9, whereas lower-risk associations were reported for AC139530.1, LINC01711, CCDC96, CYP2J2, and SPAG16. Recurrent biological themes included IL-17 signaling, ECM-receptor interaction, and focal adhesion. CA9 was the only biomarker reported in more than one included study, supporting its prioritization for validation. Although the evidence remains heterogeneous and largely hypothesis-generating, these markers may support the future validation of response-oriented therapeutic stratification in TSCC. Full article

Purpose: Due to the lack of effective local therapeutic strategies for oral squamous cell carcinoma (OSCC), this study aimed to develop a novel gelatin/lignin hydrogel loaded with mesenchymal stem cell (MSC)-derived exosomes enriched in microRNA-185 (miR-185 EV) for intraoral delivery, followed by systematic evaluation of its therapeutic efficacy and underlying molecular mechanisms. Materials and Methods: The gelatin/lignin hydrogel was prepared and subsequently loaded with miR-185 EV. The physicochemical properties of the hydrogel, including microstructure, swelling behavior, chemical composition, and rheological characteristics, were systematically evaluated. Next, the stability, viscosity, biocompatibility, and exosome release kinetics of the hydrogel were further assessed. A 4-nitroquinoline-1-oxide (4NQO)-induced mouse tongue carcinogenesis model was established to assess the in vivo antitumor activity of the hydrogel via intraoral administration. Moreover, a proteomic analysis was conducted to investigate the molecular mechanisms of miR-185 EV on OSCC. Results: The miR-185 EV-loaded gelatin/lignin hydrogel exhibited favorable physicochemical properties, stability, and biocompatibility while prolonging the tissue retention time of miR-185 EV. In vivo antitumor efficacy experiments showed that the miR-185 EV-loaded hydrogel significantly inhibited tumor occurrence and alleviated epithelial dysplasia. Immunohistochemical analyses revealed significant suppression of tumor proliferation and epithelial–mesenchymal transition (EMT) of the hydrogel. Proteomic analysis indicated that miR-185 EV suppressed OSCC progression by downregulating interleukin-1β (IL-1β), consequently inhibiting the NF-κB signaling pathway. Conclusion: The findings demonstrate the successful development of the miR-185 EV-loaded gelatin/lignin hydrogel that represents an effective nanomedicine platform for intraoral drug delivery, providing a promising strategy for the clinical treatment of OSCC. Full article

Background: Occult lymph node metastasis (OLNM) and depth of invasion (DOI) are key determinants of elective neck dissection in clinically node-negative oral tongue squamous cell carcinoma (OTSCC), yet accurate preoperative risk stratification remains challenging. This study evaluated the diagnostic performance of artificial intelligence (AI)-based predictive models for OLNM and DOI in OTSCC. Methods: A systematic review and meta-analysis were conducted in accordance with PRISMA 2020 guidelines. A structured search of PubMed identified twelve eligible studies, nine of which provided extractable 2 × 2 contingency data for inclusion in the primary bivariate meta-analysis. One additional study modeling DOI-derived pT stage was synthesized narratively. Pooled sensitivity and specificity were estimated using a bivariate random-effects model. Heterogeneity, threshold effects, and publication bias (Deeks’ test) were assessed. Methodological quality was evaluated using QUADAS-2 supplemented by an AI-specific methodological appraisal. Results: Across nine studies included in the primary meta-analysis, pooled sensitivity was 0.679 (95% CI: 0.604–0.745) and pooled specificity was 0.762 (95% CI: 0.705–0.811), with a summary AUC of 0.786. Heterogeneity was moderate for sensitivity (I² = 41.8%) and low for specificity (I² = 23.4%), with no significant threshold effect (ρ = −0.117, p = 0.776). No significant publication bias was detected (p = 0.596). Subgroup analyses showed comparable performance between OLNM-specific and general LNM models, whereas deep learning or hybrid approaches demonstrated higher accuracy than traditional machine learning methods. Notably, only one out of nine primary studies incorporated true external validation. Conclusions: AI-based models demonstrate moderate discriminative performance for predicting LNM and DOI in OTSCC and may serve as adjunctive tools in preoperative risk stratification rather than standalone decision-makers. However, the near absence of external validation, limited calibration reporting, and lack of clinician-comparator analyses substantially constrain current clinical translation. Future research should prioritize multi-center prospective validation, systematic calibration and decision-curve analyses, and adherence to TRIPOD-AI and CLAIM reporting standards. Full article

Background: Non-smoking, non-drinking (NSND) oral squamous cell carcinoma (OSCC) is increasingly recognized, yet its clinicopathologic and immune-related correlates remain incompletely defined. Methods: We retrospectively studied 243 surgically treated patients with previously untreated primary OSCC (2011–2020). Patients were classified as NSND or smoking and/or drinking (SD). Immune-modulating conditions and preoperative systemic immune–inflammatory indices (NLR, LMR, SIRI, AISI) were assessed, and overall (OS) and disease-specific survival (DSS) were analyzed. Results: Eighty-five patients (35.0%) were NSND. NSND patients were more often female (58.8% vs. 12.7%) and slightly older (median 54 vs. 50 years). Subsite distribution differed (p < 0.001): tongue (52.9%), buccal mucosa (15.3%), and floor of mouth (3.5%) in NSND versus a predominance of floor of mouth tumors in SD (34.8%). NSND tumors showed smaller diameter, lower depth of invasion, less perineural invasion (40.5% vs. 55.1%), and more frequent inflammatory infiltrate (73.8% vs. 60.1%). Immune-modulating conditions were enriched in NSND (67.1% vs. 17.7%; p < 0.001; adjusted OR 6.25, 95% CI 3.23–12.11), particularly among NSND patients >50 years (79.2%). NSND patients showed lower NLR (p = 0.01), lower SIRI and AISI (p < 0.001), and higher LMR (p < 0.001). Median OS was 81.2 months; NSND showed a trend toward improved OS (p = 0.083) and improved OS after age/sex adjustment (HR 0.64, 95% CI 0.42–0.98), but not after full clinicopathologic adjustment; DSS did not differ (p = 0.59). Conclusions: NSND OSCC exhibits a distinct clinicopathologic presentation and is strongly associated with immune-modulating comorbidity and lower tumor-associated systemic inflammatory indices, consistent with an immune-modulated clinical phenotype. Full article