Search Results (7,461)

Oral squamous cell carcinoma (OSCC) is one of the most prevalent types of cancer in the oral cavity and head and neck region. Due to its location and psychological and social implications, early detection and treatment are very important. A liquid biopsy can be used to diagnose cancer by analyzing samples of bodily fluids, such as saliva, blood, or urine, for specific molecules released by tumor cells. The objective of this study was to evaluate the use of liquid biopsy in the diagnosis of oral squamous cell carcinoma. A systematic review was carried out, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (PROSPERO: CRD420251238037). Articles taken into consideration for the review were published before 30 September 2025. The search for manuscripts for the review was conducted using PubMed, Scopus, Google Scholar, and Cochrane databases. Forty-three articles were deemed eligible for inclusion in the systematic review. Key data extracted from the studies included authorship, publication date, study location, methodology, number of participants, and reported complications. Most of the analyzed biomarkers showed promising potential for future use in liquid biopsy for OSCC diagnosis. Tumor DNA and miRNA demonstrated the highest diagnostic accuracy. The standard approach to diagnosis and planning treatment relies on tumor biopsy and diagnostic imaging. Liquid biopsy may complement this process by enabling early detection in high-risk populations and monitoring response to therapy. As such, it serves as a prognostic factor or therapeutic target, successfully identifying disease recurrence. Full article

Background/objectives: Metabolic abnormalities, independent of excess weight, may contribute to cancer risk even among individuals of normal weight, though their role remains unclear. This study sought to ascertain if metabolically unhealthy normal-weight (MUNW) individuals, generally characterized by a normal body mass index alongside the presence of metabolic abnormalities, have higher cancer risk than metabolically healthy peers, to analyze variations in risk across obesity-related cancer types, and to examine which single specific metabolic components can predict cancer independently in normal-weight individuals. Methods: Two authors systematically searched the PubMed, EMBASE, and Web of Science databases for longitudinal studies, published from inception to July 2025, that included normal-weight adults, classified participants by metabolic health status, and reported incident cancer outcomes in metabolically unhealthy versus healthy normal-weight groups. Hazard ratio (HR) estimates were extracted from each study and were pooled using random-effects inverse-variance model with empirical Bayes variance estimator. Results: Thirty-five studies involving 18,210,858 participants (56.0% females, mean age = 53.8 years) were included. A total of 280,828 new cancer cases were diagnosed during follow-up (mean = 10.6 years). In comparison with metabolically healthy normal-weight individuals, MUNW individuals had a 20% higher risk of cancer (HR = 1.20, 95% confidence interval [CI]: 1.13–1.28). Increased risks were observed for gastric cancer (HR = 1.40, 95% CI: 1.04–1.87), pancreatic cancer (HR = 1.37, 95% CI: 1.21–1.54), and colorectal cancer (HR = 1.34, 95% CI: 1.14–1.57), which were the cancer types showing statistically significant associations in subgroup analyses. Normal-weight participants presenting specific metabolic factors like central adiposity or glucose metabolism abnormalities had a 20% (HR = 1.20, 95% CI: 1.13–1.37) and 23% (HR = 1.23, 95% CI: 1.06–1.41) increased cancer risk, respectively. Conclusions: MUNW individuals are at higher risk of cancer, with specific metabolic abnormalities, particularly central adiposity and impaired glucose regulation, emerging as the factors most strongly associated with increased risk in normal-weight individuals. Routine metabolic screening and detailed phenotyping are crucial to identify these risks. Full article

Splenic lesions are common in dogs and can have important clinical implications due to the risk of rupture causing life-threatening hemorrhage, or, for neoplastic lesions, potential metastatic spread. This retrospective study analyzed 682 canine spleen samples submitted to the Regional Canine Cancer Registry in Umbria, Italy, between 2014 and 2023, aiming to characterize lesion types and explore associations with demographic factors and clinical outcomes. Lesions were classified as neoplastic or non-neoplastic. Non-neoplastic lesions were predominant (54.3%), mainly nodular hyperplasia, hematoma, and congestion, while neoplastic lesions accounted for 45.7%, with hemangiosarcoma (HSA) being the most frequent neoplasm (54.5%), followed by other sarcomas, lymphomas, and rare tumors. The mean age at diagnosis was 10.4 years, and medium-sized dogs living in urban areas were most affected. No significant differences in lesion type were observed between sexes or between purebred and mixed-breed dogs, although purebreds were more represented overall. HSA risk varied by size, sex, and breed, with large dogs and certain pure breeds showing elevated risk. Survival analysis revealed markedly reduced outcomes for dogs with HSA. These findings emphasize the utility of histopathologic diagnosis in guiding clinical management and provide insight into the epidemiology and prognosis of splenic lesions in dogs. Full article

Objective: Pain is among the most common and debilitating symptoms experienced by oncology patients and has been associated with adverse mental health outcomes, including depression and suicide. Nevertheless, the relationship between pain and suicide in oncology populations remains insufficiently characterized. A clearer understanding of this interplay is essential to guide personalized approaches aimed at reducing cancer-related burden and improving quality of life. Methods: We searched PubMed and PsycInfo without imposing limits regarding publication date using pain* AND (suicid* OR “self-harm” OR “self-injurious behavior” OR “self-inflicted injury” or “self-killing”) AND (cancer* OR oncolog* OR tumor* OR neoplasm* OR metasta*). A total of 832 articles were identified, and 15 of them were included in our review. Results: Inadequately managed pain in cancer patients is associated with a significantly elevated risk of suicidal ideation. This association is further exacerbated in individuals presenting with depressive symptoms, advanced-stage disease, or limited access to timely psychological support. These factors may interact synergistically, intensifying the emotional and cognitive burden of pain, thereby increasing vulnerability in cancer patients. Conclusions: Cancer-related pain should be conceptualized as a highly variable indicator of psychological vulnerability. Factors influencing this variability include cancer type and severity, as well as the presence of past psychopathology. These findings support the need for a personalized medicine approach, whereby pain management and psychosocial interventions are tailored to patient-specific factors such as disease stage, psychological comorbidity, and access to supportive care. Full article

Background: Pancreatic cancer (PC) is a refractory malignancy with a dismal prognosis. For unresectable PC, gemcitabine plus nab-paclitaxel (GnP) is widely used as first-line chemotherapy. During treatment, patients may require unplanned hospitalization (UPH) due to tumor progression, biliary obstruction, or chemotherapy-related adverse events. Although UPH during chemotherapy may be linked to poorer survival, its prognostic impact as a time-dependent clinical event during active treatment has not been empirically evaluated in unresectable PC. We investigated the prognostic impact of UPH occurring during first-line GnP therapy. Objective: To clarify the association between UPH during first-line GnP and overall survival (OS). Methods: We retrospectively analyzed 189 patients with histologically confirmed unresectable PC who received first-line GnP at our institution between February 2016 and February 2023. The occurrence of UPH during GnP and the reason for the first UPH were categorized. Associations with OS were assessed using the Kaplan–Meier method and Cox proportional hazards models, including a time-varying covariate (TVC) analysis. Risk factors for UPH were examined with logistic regression. Results: UPH occurred in 76 patients (40.2%) during GnP. Pancreatic head tumors and pre-treatment biliary drainage were significantly more frequent in the UPH group. Median OS was 10.88 months in the UPH group versus 19.23 months in the non-UPH group; UPH was a significant adverse prognostic factor (hazard ratio [HR] 1.97, p < 0.01). In multivariable analysis incorporating a TVC, UPH remained an independent predictor of worse prognosis (HR 3.02, p < 0.01). Reasons for first UPH were progression (n = 28), recurrent biliary obstruction (RBO; n = 26), GnP-related adverse event (AE; n = 16), and other (n = 6). Hospitalization due to progression or RBO was associated with poorer survival. Pancreatic head location was identified as a risk factor for UPH. Conclusions: UPH during first-line GnP is an independent adverse prognostic factor in patients with unresectable PC, even after accounting for TVC. In pancreatic head cancer, closer monitoring for biliary and obstructive complications may be particularly important during treatment. Full article

Background/Objectives: Preoperative body composition has been implicated as a factor affecting clinical outcomes in several types of cancer. However, there is limited evidence regarding whether preoperative body composition can predict the prognosis following gastrectomy for gastric cancer (GC). We aimed to investigate the role of preoperative body composition as a prognostic factor for overall survival (OS) and relapse-free survival (RFS) after gastrectomy for GC. Methods: This prospective study included 540 patients who underwent gastrectomy for GC at the Kanagawa Cancer Center, Japan, between December 2013 and November 2017. Preoperative body composition was assessed using the skeletal muscle index and visceral adipose tissue area derived from computed tomography scans. Patients were classified into four groups: non-sarcopenic non-obesity (NN), sarcopenic non-obesity (SN), non-sarcopenic obesity (NO), and sarcopenic obesity (SO). Results: A total of 448 patients (NN, 184; SN, 52; NO, 186; SO, 26) were included in the final analysis. In terms of OS, the SO group showed significantly worse survival than the NN group (72.1% vs. 87.6%, p = 0.01). Similarly, regarding RFS, the SO group had significantly worse outcomes than the NN group (68.4% vs. 86.2%, p = 0.007). Multivariate analysis identified SO as an independent risk factor for both OS (hazard ratio [HR], 3.18; 95% confidence interval [CI], 1.33–7.64; p = 0.01) and RFS (HR, 3.08; 95% CI, 1.36–6.95; p = 0.01). Conclusions: Preoperative SO was associated with poorer outcomes in patients undergoing gastrectomy for GC. Full article

Background: Cancer-directed treatment near the end of life may represent low-value, high-intensity care and potential medical futility, but data from middle-income countries are limited. This study used digitally documented advanced care planning (ACP) in the electronic health record (EHR) and indicators of late oncologic interventions (LOI) within 15 and 30 days before death to examine end-of-life care in Brazil. Objective: To identify factors associated with LOI near death and to explore whether documented ACP is linked to lower treatment intensity. Design: Retrospective cohort study. Setting/Participants: Adults with metastatic solid tumors who died between January 2022 and December 2023 in two oncology referral hospitals in southern Brazil and had ≥6 months of premortem EHR data. Measurements: LOI were defined as systemic anticancer therapy, radiotherapy, or oncologic surgery within 30 days (LOI-30) or 15 days (LOI-15) before death. Independent predictors were estimated by Poisson regression with robust variance. Results: Among 79 patients, 21.5% received LOI-30 and 8.9% received LOI-15. Breast and lung cancers were the most common primary sites. LOI-30 was independently associated with age < 60 years (relative risk [RR] 3.76; 95% confidence interval [CI] 1.50–9.44), higher education (RR 2.07; 95% CI 1.07–3.99), and lower platelet count (RR 0.96 per 10,000/µL; 95% CI 0.92–0.99). ACP was documented for 19% of patients and was associated with absence of LOI-30. Conclusions: Digitally visible ACP in the EHR was associated with reduced aggressive end-of-life care. Using existing EHR infrastructure to prompt and standardize ACP documentation may help align care with patient values in middle-income countries. Full article

Breast cancer and lung adenocarcinoma share common features, including female predominance and the expression of estrogen receptor (ER) and epidermal growth factor receptor (EGFR) during carcinogenesis. Patients with breast cancer have a significantly higher risk of developing second primary lung cancer than those without breast cancer. ER beta expression is associated with resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant lung adenocarcinoma, indicating a potentially important interaction between ER and EGFR. However, the mechanisms underlying this crosstalk remain poorly understood. Our clinical data showed a significant correlation between antiestrogen treatment for breast cancer and mutant EGFR expression (p = 0.021) in lung adenocarcinoma patients. In vitro, tamoxifen upregulated phosphorylated EGFR (p-EGFR) in EGFR-mutant lung adenocarcinoma cell lines. Heparin-binding EGF-like growth factor was identified as a key mediator from the ER pathway that stimulates p-EGFR. Tamoxifen counteracts estrogen’s effect and restores p-EGFR upregulation. Furthermore, coadministration of tamoxifen and the EGFR TKI gefitinib potentially inhibited p-EGFR expression in EGFR-mutant lung adenocarcinoma. Regular follow-up with chest computed tomography is recommended for patients with breast cancer. For those diagnosed with both ER-positive breast cancer and EGFR-mutant lung adenocarcinoma, combined tamoxifen and EGFR TKI therapy may offer an effective targeted treatment strategy. Full article

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have advanced the treatment of type 2 diabetes mellitus (T2DM), yet their association with cancer risk remains subject of ongoing research. Chronic pancreatitis (CP) is a well-established risk factor for pancreatic cancer, yet the impact of GLP-1 RA therapy in this high-risk population is unknown. In this study, we aimed to evaluate the association between GLP-1 RA use and pancreatic cancer incidence among patients with CP, and among those with CP and T2DM. Methods: We performed a retrospective cohort study using data from TriNetX, a healthcare database of over 150 million patients in the United States. In the first analysis, adult patients with pre-existing CP were identified and stratified by use of a GLP-1 RA (semaglutide, dulaglutide, tirzepatide, exenatide, liraglutide, lixisenatide, and albiglutide). Propensity score matching (PSM) was conducted between GLP1-RA users and non-users, matching for age, sex, race, tobacco use, alcohol use, hypertension, hyperlipidemia, obesity, and pancreatic cysts. Five-year incidence of pancreatic cancer was compared between GLP-1 RA users and non-users in the matched cohort between 2015 and 2025. We then restricted the cohort to patients with CP and T2DM and repeated this analysis. Results: We identified 89,596 patients with CP, including 3183 GLP-1 RA users and 86,413 non-users. After PSM, GLP-1 RA use was associated with a lower 5-year incidence of pancreatic cancer (hazard ratio (HR) 0.49, 95% confidence interval (CI) 0.30–0.80, p < 0.005). Similarly, amongst patients with CP and T2DM, GLP-1 RA use was associated with a lower 5-year incidence of pancreatic cancer (HR 0.53, 95% CI 0.31–0.91, p < 0.05). Conclusions: GLP-1 RA use was associated with a significantly reduced incidence of pancreatic cancer in all patients with CP, as well as the subpopulation with both CP and T2DM. Given the elevated cancer risk in CP, these findings suggest a potential beneficial effect of GLP-1RA use in this high-risk population. Prospective studies will be important to further analyze and confirm this potential benefit. Full article

Background: Liver cirrhosis increases perioperative risk in colorectal cancer surgery, yet data on long-term outcomes remain limited. In this study, we evaluated postoperative morbidity, mortality, and survival in cirrhotic patients. Methods: In this single-center retrospective cohort, 53 cirrhotic patients undergoing elective colectomy or proctectomy (2011–2022) were propensity score-matched 1:1 with non-cirrhotic controls. Perioperative variables, complications, and survival were analyzed. Subgroup analyses were performed for right hemicolectomy and non-right hemicolectomy procedures. Kaplan–Meier and logistic regression analyses were implemented to assess outcomes and risk factors. Results: Cirrhotic patients had higher preoperative MELD-Na scores and lower albumin and hemoglobin levels. They experienced greater blood loss, longer operative times, more ICU admissions, and higher rates of major complications (18.9% vs. 3.8%, p = 0.01). Mortality was higher at in-hospital (7.5% vs. 0%), 3-month (9.4% vs. 0%), and 60-month (66% vs. 28.3%) intervals, and these patients’ overall survival was shorter (70.7 vs. 116.8 months, p < 0.001). The subgroup analysis showed that the adverse impact of cirrhosis persisted for both right hemicolectomy and non-right hemicolectomy procedures, with significantly worse long-term survival in cirrhotic patients. Postoperative complications after right hemicolectomy did not differ significantly between groups. Among cirrhotic patients, Child–Turcotte–Pugh class B predicted worse survival than class A (40.1 vs. 84.8 months, p = 0.006). Preoperative hypoalbuminemia (<3.5 g/dL) independently predicted long-term mortality (HR = 3.93). Conclusions: Elective colorectal surgery in patients with cirrhosis is associated with increased perioperative complications and significantly reduced long-term survival. However, postoperative outcomes after right hemicolectomy in cirrhotic patients were comparable to those of non-cirrhotic patients, despite their persistently poorer long-term survival. Optimization of nutritional status and careful preoperative assessment of hepatic reserve are essential to improving outcomes in this high-risk population. Full article

Background and Objectives: Contrast-enhanced mammography (CEM) provides both morphological and functional information and may reflect breast cancer biology similarly to Magnetic Resonance Imaging (MRI). Materials and Methods: This single-center retrospective study included 399 women with Breast Imaging Reporting and Data System (BI-RADS) category 0 screening mammograms who subsequently underwent CEM. A total of 76 malignant lesions (68 invasive cancers, 8 ductal carcinoma in situ (DCIS)) with complete imaging and pathology data were analyzed. Invasive cancers were classified into luminal A, luminal B, luminal B/Human Epidermal Growth Factor Receptor 2 (HER2)-positive, HER2-enriched, and triple-negative, and grouped as luminal (Group 1) versus HER2-positive/triple-negative (Group 2). Results: Luminal subtypes predominated (47 of 68, 69%), while 21 of 68 (31%) were HER2-positive or triple-negative. Most cancers appeared as masses with spiculated margins and heterogeneous enhancement. Significant differences were observed in mass shape (p = 0.03) and internal enhancement (p = 0.01). Luminal tumors were more often irregular and spiculated with heterogeneous enhancement, whereas the HER2-positive/triple-negative tumors more frequently appeared round with rim or homogeneous enhancement. Deep learning-derived malignancy scores (iCAD ProFound AI^®) demonstrated good diagnostic performance (area under the curve (AUC) = 0.744, 95% confidence interval (CI) 0.654–0.821, p < 0.001). The median AI score was significantly higher in malignant compared with benign lesions (70% [interquartile range (IQR) 47–93] vs. 38% [IQR 25–61]; Mann–Whitney U test, p < 0.001). Among malignant lesions, iCAD scores varied across molecular subtypes, with higher median values observed in Group 1 versus Group 2 (87% vs. 55%), although the difference was not statistically significant (Mann–Whitney U test, p = 0.35). Conclusions: CEM features mirrored subtype-specific phenotypes previously described with MRI, supporting its role as a practical tool for enhanced tumor characterization. Although certain imaging and AI-derived parameters differed descriptively across subtypes, no statistically significant differences were observed. As deep-learning models continue to evolve, the integration of AI-enhanced CEM into clinical workflows holds strong potential to improve lesion characterization and risk stratification in personalized breast cancer diagnostics. Full article

Background/Objectives: Effective screening for oral cancer (OC) remains challenging. Inaccuracies contribute to delayed diagnosis and poor outcomes. Tobacco-related changes in oral mucosa may compromise the accuracy of oral screening approaches, and, in emerging “smart” screening modalities, they may overshadow the influence of other predictive variables. The objective of this study was to evaluate the screening accuracy of an imaging- and risk factor-based OC screening platform in individuals practicing different types of tobacco usage. Methods: 318 subjects who had previously screened positive for increased OC risk were recruited and sorted into “tobacco smoker”, “tobacco vaper”, “tobacco chewer”, “hookah user”, “multiple tobacco usage”, or “tobacco non-user” groups. Next, demographic information, risk factors, outcome of clinical examination, as well as AFI and pWLI were recorded using a prototype OC screening platform. The OC risk assessment outcome from the OC screening platform was compared to that from an oral medicine specialist. Results: The screening platform demonstrated high sensitivity in tobacco chewers and hookah users, and it also exceeded 90% in smokers, vapers, and multi-product users. In tobacco non-users, 80% screening sensitivity was recorded. Screening specificity was considerably better in tobacco non-users than in the tobacco-user groups, and low in tobacco chewers (33.3%), vapers (55.6%), and smokers (62.5%). Across all groups, agreement between the screening platform outcome and specialist evaluation exceeded 80%. Significant differences in probe accuracy were noted between tobacco non-users and users (p < 0.05), except for tobacco vapers. Conclusions: These findings highlight the need to consider the effects of type of tobacco use on the OC screening approach, and to integrate these variables into imaging-and risk-factor-based algorithms for OC screening. Full article

Objective: To evaluate population-level temporal relationships between modifiable lifestyle factors and rising breast, colorectal and uterine cancer incidence rates among females under 50 years old. Methods: This retrospective ecological study utilized data from the United States Cancer Statistics (USCS) for cancer incidence, the National Health and Nutrition Examination Survey (NHANES) for health-related behaviors, and the Behavioral Risk Factor Surveillance System (BRFSS) for physical activity. Modifiable lifestyle factors analyzed included obesity (BMI ≥ 30 kg/m²), smoking, alcohol use, fiber and saturated fat intake, caloric intake, and physical activity. Trends were assessed using average annual percent change (AAPC), and population-level correlations between cancer incidence and lifestyle factors were evaluated using Pearson correlation coefficients. Results: Between 2001 and 2018, 914,659 breast, 144,130 colorectal, and 124,399 uterine cancer cases were identified. The largest increases in cancer incidence occurred in age groups under 30 years old. Colorectal cancer increased by 6.9%, followed by uterine cancer at 4.8% and breast cancer at 1.7%, all p < 0.001. When examining this age group by race, colorectal cancer increased by 8.0% (p < 0.001) annually in White women aged 20–24 years, while uterine cancer rose 4.8% (p < 0.001) in Hispanic women in the 20–24 and 25–29 year age groups. Breast cancer also increased by 2.0% (p < 0.001) per year in White women 25–29 years old. Smoking rates decreased, and alcohol consumption and obesity rates increased. No significant correlation was found between cancer incidence and smoking, caloric intake, saturated fat, or physical activity. A moderate positive correlation was identified between alcohol use and cancer risk (r = 0.55–0.67, p < 0.05). Obesity prevalence showed strong population-level temporal correlation with cancer incidence for all three cancers with stratified analysis demonstrating the strongest correlations in patients with class III obesity. Conclusions: From 2001 to 2018, the incidence of breast, colorectal, and uterine cancers increased most sharply among women under 30 years of age. Over the same period, obesity prevalence in this population also increased. These population-level observations are hypothesis-generating and require confirmation in individual-level, prospective studies to determine whether and how obesity and other lifestyle factors influence early-onset cancer risk. Full article

Background: Neuroblastoma is the most common extracranial solid malignancy in infants and children. High-risk neuroblastoma patients are commonly treated with temozolomide (TMZ), which typically exhibits a poor therapeutic response. Serotonin, also known as 5-hydroxytryptamine (5-HT), plays various essential functions in the human body. In the central nervous system, it serves as a neurotransmitter. Beyond its physiological roles, 5-HT has recently been identified as a potential growth factor for several human tumors, including gliomas and carcinoid tumors. Recent literature has demonstrated that 5-HT receptor antagonists can inhibit the growth of cancer cells. Furthermore, both 5-HT receptors and their antagonists have been identified as potential anticancer agents, suggesting their significance in the development of new treatment strategies. Objectives: The primary aim of this study was to examine the effects of 5-HT and 5-HT antagonists on tumor (neuroblastoma (SH-SY5Y)) and healthy cells (microglia (HMC3)) and determine the impact of their interaction with the anticancer agent TMZ on cell proliferation/viability and migration. Methods: The study explored the interaction between 5-HT, the 5-HT antagonist granisetron (GRN), the anticancer agent TMZ, and their combinations, specifically assessing their influence on cell proliferation, viability, and migration. Results: As a result, the single and combined applications of 5-HT, TMZ, and GRN, a 5-HT antagonist, inhibited cell growth and proliferation in SH-SY5Y, causing decreased cell viability. Additionally, the combination of 5-HT and GRN increased the efficacy of TMZ. Conclusions: The study findings revealed that 5-HT and 5-HT antagonists may have therapeutic effects by exhibiting antiproliferative effects in SH-SY5Y cells at high concentrations. Full article

Background: Lung adenocarcinoma (LUAD) exhibits pronounced cellular and molecular heterogeneity that shapes tumor progression and therapeutic response. Although nucleotide metabolism is essential for sustaining tumor proliferation and coordinating immune interactions, its single-cell heterogeneity and clinical implications remain incompletely defined. Methods: We integrated a publicly available scRNA-seq dataset derived from independent LUAD patients to construct a comprehensive LUAD cellular atlas, identified malignant epithelial cells using inferCNV, and reconstructed differentiation trajectories via Monocle2. Cell–cell communication patterns under distinct nucleotide metabolic states were assessed using CellChat. A nucleotide metabolism-related signature (NMRS) was subsequently developed across TCGA-LUAD and multiple GEO cohorts using 101 combinations of machine learning algorithms. Its prognostic and immunological predictive value was systematically evaluated. The functional relevance of the key gene ENO1 was further verified through pan-cancer analyses and in vitro experiments. Results: We identified substantial nucleotide metabolic heterogeneity within malignant epithelial cells, closely linked to elevated proliferative activity, glycolytic activation, and increased CNV burden. Pseudotime analysis showed that epithelial cells gradually acquire enhanced immune-modulatory and complement-related functions along their differentiation continuum. High-metabolism epithelial cells exhibited stronger outgoing communication—particularly via MIF, CDH5, and MHC-II pathways—highlighting their potential role in shaping an immunosuppressive microenvironment. The NMRS built from metabolism-related genes provided robust prognostic stratification across multiple cohorts and surpassed conventional clinical parameters. Immune profiling revealed that high-NMRS tumors displayed increased T-cell dysfunction, stronger exclusion, higher TIDE scores, and lower IPS, suggesting poorer responses to immune checkpoint blockade. ENO1, markedly upregulated in high-NMRS tumors and functioning as a risk factor in several cancer types, was experimentally shown to promote invasion in LUAD cell lines. Conclusions: This study delineates the profound impact of nucleotide metabolic reprogramming on epithelial cell states, immune ecology, and malignant evolution in LUAD. The NMRS provides a robust predictor of prognosis and immunotherapy response across cohorts, while ENO1 emerges as a pivotal metabolic–immune mediator and promising therapeutic target. Full article