The roles of eosinophil extracellular traps (EETs) in cancer have not been investigated. This research aims to unearth the association between EETs and clinical outcomes in pan-cancer. From the Cancer Genome Atlas (TCGA) program, a 28-gene EETs score was constructed. Overall, higher EETs scores indicated shorter overall survival. EETs were significantly correlated to various pro-tumor processes, including extracellular matrix remodeling, IL-17 signaling, M2 macrophage polarization, and Treg differentiation. Immune suppressive M2 macrophages infiltrated more in the tumor microenvironment (TME), while cytotoxic cells (CD8 T and NK cells) were fewer. EETs-gene expression correlated with multiple T cell co-inhibitors. Target molecules of immune checkpoint inhibitors (ICIs) were not in proximity to the EETs disease module. Drugs against IL-5, IL-5RA, CCL-11 and IL-33 scored highly in perturbation of the disease module. Therefore, the EETs formation was coordinated with the adverse clinical outcomes and TME alternations in cancer. The role of EETs and anti-eosinophil therapy in cancer deserve further investigation in the era of immunotherapy.

Recent studies have increasingly focused on the role of fungi, including Candida albicans, in carcinogenesis. Since C. albicans is a component of the human microbiota, particularly on the skin, we investigated its effect on the phenotype and signalling pathways of melanoma cells. Assays for migration, adhesion, angiogenesis, and hepatic metastasis showed that C. albicans promotes a more malignant phenotype in melanoma cells. At the transcriptomic level, C. albicans increased the expression of VEGF (Vegfa), and genes associated with MAPK and HIF-1 signalling pathways, and with aerobic glycolysis. Further in vitro analysis revealed that TLRs and EphA2 receptors are involved in the recognition of live C. albicans, stimulating VEGF secretion and expression of the AP-1 transcription factor component c-Fos through p38-MAPK and HIF-1α. These pathways also regulate the expression of other AP-1 constituents such as Atf3, Jun, and Jund. Moreover, p38-MAPK regulates glycolytic genes like Hk2, Slc2a1, and Eno2. In conclusion, C. albicans activates the p38-MAPK/c-Fos/AP-1 and HIF-1/HIF-1α/c-Fos/AP-1 pathways in melanoma cells, promoting a pro-angiogenic environment and metabolic reprogramming. Therefore, this study clarifies the impact of C. albicans on melanoma cells, which can lead to the use of antifungal therapies as complementary to traditional treatments for melanoma.

CD2-associated protein (CD2AP) is an adapter protein that stabilizes the actin cytoskeleton and is closely linked to disulfidptosis. However, its functional role in hepatocellular carcinoma (HCC) progression and disulfidptosis remains undefined. Herein, pan-cancer multiomics analyses were performed on 33 malignancies from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) cohorts to evaluate CD2AP expression patterns, prognostic significance, and interactions with the tumor immune microenvironment. Clinical validation was performed using 70 HCC specimens, with qRT-PCR analysis and survival assessments. CD2AP expression was significantly elevated in tumor tissues across multiple cancer types and correlated with poor survival outcomes. In tumor tissues, high CD2AP expression positively correlated with the expression of immune checkpoints, including HAVCR2, CTLA4, CD274, TIGIT, and PDCD1. Additionally, qRT-PCR analysis of 70 HCC patients in our cohort confirmed a marked upregulation of CD2AP in HCC tumor tissues. Specifically, Kaplan-Meier analysis further revealed that high CD2AP expression was associated with reduced overall survival and recurrence-free survival in our HCC cohort. Functional experiments demonstrated that CD2AP silencing inhibited HCC cell proliferation and enhanced disulfidptosis susceptibility in SLC7A11-high cells, likely via NADPH depletion and actin network disruption. In conclusion, our findings indicate that CD2AP functions as an oncogene in HCC, promoting tumor progression by regulating disulfidptosis. This study provides novel insights into CD2AP as a potential prognostic biomarker and therapeutic target for HCC.

In patients with advanced non-small cell lung cancer (NSCLC), MET exon 14 (METex14) skipping mutations are rare and are associated with a poor prognosis. Capmatinib, a selective oral MET inhibitor, was recently approved for the treatment of advanced METex14 skipping NSCLC. However, data from real-world experiences are limited. This was a retrospective analysis using real-world data from Italian patients with advanced METex14 skipping NSCLC who had received at least one treatment with immunotherapy and/or platinum-based chemotherapy and received compassionate use treatment with capmatinib. Patient characteristics, treatment details, discontinuations, and adverse events are reported. Overall, 53 patients received capmatinib after receiving treatment with immunotherapy and/or platinum-based chemotherapy in Italy. Patients had a median age of 74 years, mostly metastatic disease (92.5% of patients), and previously received one (66.0%) or more (2: 28.3%; 3: 5.7%) lines of standard treatment (immunotherapy and/or platinum-based chemotherapy). Most patients (98.1%) started treatment with capmatinib at the full recommended dose of 400 mg twice daily and 77.4% did not require a dose reduction. Twenty-four patients (45.3%) discontinued treatment; the most frequent reason for discontinuing treatment was disease progression, with a median estimated time to treatment discontinuation of 15.2 months. This real-world retrospective analysis confirms that capmatinib is a valuable treatment option for difficult-to-treat METex14 skipping NSCLC, in agreement with the data from the registration trial.

Gastric cancer (GC) presents with insidious early symptoms that lack distinctiveness. Coupled with insufficient screening awareness and limited diagnostic methods, these symptoms are difficult to distinguish from manifestations of benign conditions including gastritis and gastric ulcers, leading patients to seek medical attention only after advanced-stage symptoms develop. Traditional serum markers exhibit low positivity and specificity in early-stage GC; therefore, actively identifying novel molecules for combined diagnosis in conjunction with traditional biomarkers proves essential for the early diagnosis of GC. tRNA-derived small RNAs (tsRNAs), a novel category of non-coding RNAs (ncRNAs), exhibit promise as liquid biopsy indicators and can engage in the pathological processes of cancer through diverse molecular pathways. In this study, we seek to identify tsRNAs that may facilitate the diagnosis and prognostic surveillance of GC, thus offering a substantial scientific foundation for enhancing the precision diagnosis and therapy of GC, as well as clarifying its pathological mechanisms.In this study, microarray detection technology was employed to analyze serum samples from 5 patients with stage ⅠGC, 5 with stage II-III GC, 5 with superficial gastritis, and 5 healthy donors. Subsequently, tsRNAs with significantly upregulated expression in GC serum were identified by comparative analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to screen tRF-18-HR05X6D2 as a target for further analysis in tissues, serum, and cells. The stability of tRF-18-HR05X6D2 detection performance was evaluated through room-temperature incubation and repeated freeze-thaw cycle experiments. tRF-18-HR05X6D2 was identified and analyzed via agarose gel electrophoresis (AGE), Sanger sequencing, and RNA isolation methods. qRT-PCR was applied to determine the differential expression levels of tRF-18-HR05X6D2 in serum from a large cohort of clinical specimens. The correlation between tRF-18-HR05X6D2 expression levels and clinicopathological parameters was assessed via chi-square test, complemented by the construction of receiver operating characteristic (ROC) curves, on the other hand, was employed to evaluate its diagnostic performance. We predict its downstream target genes by bioinformatics analysis. Finally, we explored its function in cells through in vitro experiments.The expression of tRF-18-HR05X6D2 was found to be elevated in the serum of GC patients, as well as in GC tissues and GC cell lines. Serum levels of tRF-18-HR05X6D2 were associated with tumor dimensions, invasive depth, lymph node involvement, TNM classification, and vascular infiltration. Following surgical treatment, tRF-18-HR05X6D2 expression was decreased. The combination of tRF-18-HR05X6D2 with carcinoembryonic antigen (CEA), carbohydrate antigen 72-4 (CA72-4), and carbohydrate antigen 19-9 (CA19-9) can significantly improve the diagnostic efficacy of GC. Cell function experiments suggested that tRF-18-HR05X6D2 could promote the proliferation, migration, and invasion of GC cells. Based on the aforementioned results, tRF-18-HR05X6D2 shows promise as a diagnostic indicator for GC.tRF-18-HR05X6D2 exhibits promise not just as a non-invasive marker for the early diagnosis of GC, but also as a predictor of disease progression.

Chronic lymphocytic leukemia (CLL) is a type of cancer that affects the blood and bone marrow, specifically involving the overproduction of abnormal lymphocytes. Using two independent datasets (GSE249956 and GSE98206), differentially expressed genes (DEGs) were identified between ibrutinib-resistant and sensitive CLL samples. Protein-protein interaction (PPI) network analysis revealed key hub genes related to resistance. Three common hub genes were shared across datasets: PDCD1, CD1C, and ITGB2. PDCD1, encoding the immune checkpoint protein PD-1, was selected for deeper investigation due to its important role in immune regulation and relevance in drug resistance. Post-transcriptional regulation of PDCD1 was explored by the construction of competing endogenous RNA (ceRNA) networks linking lncRNAs and miRNAs that may modulate PDCD1 expression, indicating complex upstream regulatory mechanisms. Transcription factors potentially regulating PDCD1 were identified, suggesting layers of transcriptional control contributing to ibrutinib resistance. Drug-gene interaction analysis showed that although PDCD1 is not directly targeted by ibrutinib. This implicates immune checkpoint blockade as a promising therapeutic strategy to overcome or complement resistance in CLL. In the broader context, PD-1 expression in CLL cells is linked to active proliferation and immune escape. Overall, our findings emphasize PDCD1's central role in ibrutinib resistance through immune checkpoint pathways and support the rationale for combining BTK inhibitors with immune checkpoint blockade therapies in resistant CLL cases.

This study examines the function of chromatin-remodeling genes (CRGs) in nasopharyngeal carcinoma (NPC), with an emphasis on their potential as prognostic and diagnostic biomarkers. We examined gene expression information collected from multiple datasets (GSE12452, GSE53819, GSE61218, and GSE102349) using a multi-stage methodology; we also performed differential expression, weighted gene co-expression network analysis, and functional enrichment analyses to identify pathogenic CRGs. A prognostic signature of six key genes-CDC6, EZH2, PHF14, PRC1, RAD54B, and UHRF1-was developed through machine learning methods and further validated in independent datasets. The identified genes were used to build a diagnostic model, which performed well (AUC > 0.8) in both training and validation cohorts. This model was further refined using a nomogram and demonstrated high clinical utility, as confirmed by decision curve analysis and calibration curves. Furthermore, the study of immune infiltration showed a strong correlation between immune cell types and diagnostic genes, while single-cell RNA sequencing highlighted functional differences across epithelial subpopulations in NPC. Notably, experimental validation of PHF14 indicated its involvement in NPC malignancy, with downregulation of PHF14-suppressing cell migration, invasion, and proliferation. These discoveries give fresh perspectives on the molecular processes of NPC and offer potential biomarkers for clinical diagnosis and prognosis.

The cardinal features of triple-negative breast cancer (TNBC) are that it is aggressive and does not express estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, presenting significant therapeutic challenges. Recent advances have identified immune checkpoint inhibitors (ICIs), especially anti-PD-1/PD-L1 agents, as promising treatments for TNBC. Tumor mutational burden (TMB) has been implicated as a promising approach for predicting ICI responses. This review examines the current evidence in favor of TMB as a biomarker, its relationship with ICI efficacy, and future directions in TNBC therapy. We explore the mechanisms linking high TMB to enhanced neoantigen presentation, which leads to improved immune responses and better patient outcomes with ICIs. Additionally, we discuss the role of combination therapies involving ICIs with chemotherapy or poly(ADP-ribose) polymerase inhibitors, and how TMB can guide treatment personalization in TNBC. While TMB shows promise, further research is needed to establish standardized measurement techniques and cutoffs, enhancing its clinical utility in predicting ICI response. Future studies focusing on tumor microenvironment interactions and resistance mechanisms are crucial for advancing precision oncology in TNBC.

Malignant pleural mesothelioma (MPM) is a rare but aggressive thoracic malignancy primarily linked to asbestos exposure. Despite advances in research, the prognosis of MPM remains poor, and there is a lack of efficient and precise prognostic assessment tools. Its insidious onset, limited treatment options, and high resistance to therapy contribute to poor clinical outcomes and underscore the urgent need for reliable prognostic biomarkers. To address this gap, we integrated multi-omics data to identify a prognostic gene set for MPM and subsequently developed a prognostic model aiming to improve the clinical outcomes of this disease. Transcriptomic data from TCGA were used to identify genes related to prognosis and tumor stage in malignant pleural mesothelioma (MPM), followed by construction of a prognostic model via LASSO-Cox regression and external validation using a GEO dataset. The model was then integrated with DNA methylation and SNP data for GO enrichment analysis. Chemotherapy drug IC50 data from MPM cell lines were correlated with model gene expression to evaluate associations between risk scores and drug sensitivity, which were further validated using TCGA clinical response data. Finally, the model's impact on the immune microenvironment was assessed using single-cell RNA-seq data, and its predictive value for immunotherapy response was validated in an independent MPM immunotherapy cohort. Our novel prognostic model demonstrated consistent performance in both the training and validation cohorts. Patients with high-risk scores had poorer outcomes, with AUC values exceeding 0.8 and reaching 0.9 for 3 year survival prediction. The risk score accurately reflected biological processes such as tumor proliferation and metastasis in mesothelioma. It was also closely associated with clinical responses to radiotherapy and chemotherapy, with low-risk patients showing greater sensitivity and lower drug IC50 values. Additionally, the risk score correlated positively with tumor immune activity and was predictive of immunotherapy response. In conclusion, our prognostic model shows strong and reliable predictive power for patient survival and treatment response in malignant pleural mesothelioma. It not only reflects key tumor biological processes but also serves as a potential tool for guiding personalized therapy, including chemotherapy, radiotherapy, and immunotherapy.

Patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR).For driver mutations, the use of EGFR tyrosine kinase inhibitors (TKIs) is the standard treatment, but acquired resistance is inevitable. There is currently no standard treatment for first-line TKI-resistant NSCLC patients. In recent years, although immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for advanced NSCLC without driver gene mutations, the clinical efficacy of these agents in patients with advanced NSCLC harboring EGFR mutations remains limited. Whether ICIs are suitable for patients with EGFR-mutated advanced NSCLC still warrants further investigation.This review summarizes several clinically utilized ICIs, presents clinical evidence regarding the efficacy of immunotherapy in patients with EGFR-mutated advanced NSCLC, and identifies EGFR-mutated subpopulations that may benefit from ICI treatment. On this basis, we explored more effective therapeutic strategies to extend the benefits of immunotherapy to a larger cohort of patients with EGFR-mutated NSCLC.

Cellular senescence is a hallmark of cancer and induces senescence-associated inflammatory responses in the tumor microenvironment (TME). CDKN1A, an important cellular senescence marker, plays significant roles in cell proliferation, invasion, migration, and apoptosis. Previous studies have implied its drug resistance role in certain cancer types. However, its impact on immunotherapy efficacy in advanced LUAD remains unclear. Using TCGA and SU2C-MARK cohorts, we investigated CDKN1A's biological features in advanced LUAD, analyzing pathway regulation, immune infiltration, and immunotherapy associations. Single-cell RNA sequencing (GSE148071) validated TME and cellular communication differences between CDKN1A high/low expressing tumors in advanced LUAD. CDKN1A expression was positively associated with immunosuppressive environment including extracellular matrix, cancer-associated fibroblasts (CAFs) and myeloid-derived suppressor cells (MDSCs) in advanced LUAD for both TCGA and SU2C-MARK cohorts (P < 0.05). CDKN1A showed significantly positive correlations with many senescence genes in advanced LUAD (P < 0.05), which were also positively associated with endothelial cells, epithelial cells, fibroblast cells and macrophages, but negatively associated with immune cells (P < 0.05). In multivariable cox regression, patients with high CDKN1A expression had worse OS (HR = 2.74, 95% CI = 1.31-5.73, P = 0.007) and PFS (HR = 1.78, 95% CI = 1.01-3.11, P = 0.045) than those with low CDKN1A expression when treated with immunotherapy. In contrast, the high CDKN1A expression was not associated with PFS and OS in the TCGA cohort, in which the LUAD patients received standard chemotherapy, suggesting the immunotherapy predictive role instead prognostic role of CDKN1A. Moreover, single-cell analysis revealed that CDKN1A highly expressed tumors were accompanied by an enrichment of stromal and endothelial cells within the tumor microenvironment, along with enhanced activity of SMAD3/4, the downstream transcription factors of TGFB signaling. These tumors exhibited increased cell-cell communication with stromal cells (COL1A1/COL1A2-ITGA1/ITGB1/SDC1) and endothelial cells (NAMPT-ITGAS/ITGB1/INSR). CDKN1A expression was associated with cellular senescence, immunosuppressive environment and exhibited resistance to immunotherapy in advanced LUAD, suggesting a potential combination strategy with senolytic or senomorphic therapies to overcome immunotherapeutic resistance in the future.

Acute myeloid leukemia (AML) is a malignancy involving the blood and bone marrow, marked by the uncontrolled growth and development of myeloid cells. LncRNA small nucleolar RNA host gene 11 (SNHG11) is aberrantly expressed in various cancers. Objective of current research was to explore the SNHG1 expression in AML patients and further explore its role and mechanisms in AML cell biology.

The ubiquitin proteasome system serves as one of the key protein degradation pathways for cellular homeostasis, and its E3 ubiquitin ligase regulates cell survival and death by specifically recognizing the degradation of target proteins. Ferroptosis, a regulated cell death driven by membrane lipid peroxidation, is modulated by the ubiquitin-proteasome system through E3 ubiquitin ligases targeting specific proteins. Based on the screening of 571 UPS-related genes in previous studies, we further selected a subset of 286 E3 ligases for analysis. Subsequently, cell division cycle 26 (CDC26) was identified as an inducer of ferroptosis in in human pancreatic ductal adenocarcinoma (PDAC) cells. CDC26 expression is downregulated during ferroptosis in PDAC. Functionally, CDC26 overexpression enhances ferroptosis by increasing reactive oxygen species (ROS) and lipid peroxidation, while suppressing cell proliferation and invasion. Mechanistically, CDC26 promotes the ubiquitin-mediated degradation of solute carrier family 7 member 11 (SLC7A11), a key ferroptosis inhibitor, and indirectly inhibits the cell cycle, further sensitizing cells to ferroptosis. These findings establish CDC26 as a ferroptosis mediator, highlighting its role in the ubiquitin-proteasome-ferroptosis network and its potential as a therapeutic target for pancreatic cancer.

Recent studies have emphasized the contributions of cancer-associated fibroblasts (CAFs) to cancer initiation, immune suppression, and treatment resistance. Advancing our molecular understanding of CAFs is therefore crucial to improve outcomes for colorectal cancer (CRC) patients. In this study, integrative analysis of single-cell RNA-sequencing data from GSE166555 and GSE144735 identified ten cellular subpopulations. Consensus clustering exhibited four distinct CAF subtypes, with the C4 subtype showing elevated expression of most CAF-specific genes, and predominant enrichment of stromal activation signatures. Functional enrichment analysis of C4-specific transcripts showed dominant enrichment in extracellular matrix (ECM) remodeling pathways. Univariate Cox regression analysis identified eight survival-critical genes, among which LHFPL6 demonstrated the highest specificity and sensitivity for discriminating C4 (AUC = 0.98). Multiple cohorts further confirmed that higher LHFPL6 expression was associated with worse survival outcomes across diverse clinical endpoints (all p < 0.05). Multivariate Cox regression analysis established LHFPL6 as an independent prognostic factor (HR = 5.889, p = 0.017). Additionally, LHFPL6 was predominantly expressed in fibroblasts and positively correlated with CAF scores. Co-expressed genes of LHFPL6 showed significant enrichment in ECM signatures and epithelial-mesenchymal transition (EMT) pathways. Functional experiments using CAF-tumor co-culture models demonstrated that LHFPL6 knockdown suppressed SW480 malignant behaviors, as evidenced by reduced proliferation, migration, and invasion. This study demonstrates that LHFPL6 serves as a promising prognostic biomarker and potential therapeutic target for CRC.

To elucidate the immunological mechanisms underlying T cell exhaustion in papillary thyroid carcinoma (PTC) by integrating bulk and single-cell transcriptomic data, with a particular focus on the NECTIN-TIGIT interaction as a potential driver of immune evasion. Papillary thyroid carcinoma, while often indolent, can recur or progress in certain patients. Increasing evidence suggests that immune evasion within the tumor microenvironment (TME) plays a central role in PTC pathogenesis. Among the various immune checkpoint pathways, the NECTIN-TIGIT axis has emerged in other cancers as a key mediator of T cell dysfunction; yet, its role in PTC remains poorly characterized. We conducted an integrated analysis of publicly available bulk RNA-sequencing and single-cell RNA-sequencing (scRNA-seq) datasets from the gene expression omnibus (GEO). Differential gene expression, cell-type annotation, exhaustion marker profiling, and ligand-receptor interaction analyses were employed to investigate immune cell states and intercellular signaling. Drug sensitivity data from multiple pharmacogenomic databases were used to assess therapeutic implications. Our analysis revealed a high expression of TIGIT and associated exhaustion markers (PDCD1, CTLA4, and TOX) in PTC-infiltrating T cells, alongside a dominant presence of NECTIN2/3 in epithelial and endothelial compartments. The NECTIN-TIGIT interaction was found to suppress CD226 co-stimulatory signaling, promoting T cell exhaustion. Endothelial cells were identified as key ligands senders, creating an immunosuppressive microenvironment. Drug sensitivity correlations further suggested that TIGIT-mediated exhaustion may influence therapeutic responsiveness. This study identifies the NECTIN-TIGIT axis as a novel immunoregulatory pathway contributing to T cell exhaustion in PTC. These findings provide mechanistic insights into immune evasion and suggest NECTIN-TIGIT signaling as a potential biomarker and therapeutic target. Future wet-laboratory validation and clinical studies are needed to confirm the translational relevance of this axis in thyroid cancer management.

Gastric cancer (GC) presents striking survival disparities: 85-100% for early-stage versus only 5-20% for advanced disease. Glucose metabolic reprogramming (GMS)-a cancer hallmark linked to the Warburg effect-fuels tumor progression and immune evasion via lactate. This study uses multi-omics data to delineate GMS heterogeneity and its clinical relevance in GC. Single-cell, spatial, and bulk transcriptomic data were integrated. BayesPrism deconvoluted bulk data, CytoTRACE2, CellChat, and NicheNet analyzed cell trajectories, communication, and ligand-receptor regulation, respectively. MOVICS performed multi-omics (mRNA, methylation, mutation, and lncRNA) clustering of TCGA-STAD. Mime1 integrated machine learning to build a prognostic model based on GMS-related genes and CS2/TOP2A features. Differential expression and functional enrichment explored mechanisms. Verification of expression differences in key genes using qPCR. In gastric cancer research, GMS scores exhibit significant enrichment. Single-cell analysis identified a TOP2A+ epithelial subtype characterized by high GMS scores, strong stemness, elevated proliferative activity, and poor prognosis. Further analysis suggests this subtype may be regulated by the EFNB2-EPHB2 signaling pathway originating from GABRP⁺ cells, activating cell cycle pathways via ligands such as CKLF. Multi-omics clustering defined the CS2 subtype, exhibiting enrichment in GMS score, cell cycle, and glucose metabolism pathways and correlating with poor prognosis. A prognostic model constructed using eight genes demonstrated robust predictive performance across TCGA and multiple independent cohorts, with high-risk patients potentially exhibiting 'cold tumor' characteristics. Among these, the core gene SH3BP1 was identified as a potential tumor suppressor (HR = 0.87), whose overexpression correlated with lower tumor stage and enhanced CD8⁺ T cell killing and infiltration. This study is the first to systematically characterize GMS heterogeneity in GC via integrated multi-omics. It identifies the aggressive TOP2A⁺ subtype, establishes the clinically relevant CS2 classification, and develops a robust 8-gene prognostic model-useful for stratifying patients with immunologically "cold" tumors. Critically, tumor suppressor SH3BP1 (a key regulator) correlates with reduced tumor progression and enhanced CD8+ T cell anti-tumor immunity when highly expressed. These findings underscore that SH3BP1 may represent a promising therapeutic target for precise intervention in GMS-immune interactions in GC.

Clear cell renal cell carcinoma (ccRCC), a prevalent renal malignancy with limited early symptoms, demonstrates immunotherapy sensitivity in advanced stages. This study investigates how exhausted T cells drive ccRCC progression through single-cell transcriptomics. Re-analysis of a single-cell transcriptomic dataset was performed through dimensionality reduction and clustering to annotate cells into distinct populations, followed by comprehensive characterization of cellular composition and subset-specific features. Prognostically relevant genes were identified via differential gene expression (DGE) analysis, and a nomogram prediction model was constructed using Cox regression analysis, with validation through Kaplan-Meier (KM) survival curves and risk score plots. Functional annotation of SOCS3+ exhausted T cells was achieved via gene ontology (GO) and reactome pathway enrichment analyses. Cell-cell communication networks involving SOCS3+ exhausted T cells were delineated using ligand-receptor interaction profiling. Single-cell transcriptomic data were annotated into nine distinct cellular populations, among which SOCS3+ exhausted T cells demonstrated significant prognostic relevance. A nomogram prediction model incorporating SOCS3 and N4BP1 effectively stratified patients into low- and high-risk groups with superior prognostic predictive power compared to conventional parameters. Cell-cell communication analysis revealed that SOCS3+ exhausted T cells interact with myeloid cells through the MIF signaling pathway. Integrated single-cell transcriptomic analysis demonstrates that SOCS3+ exhausted T cells promote tumor resistance to cytotoxic killing and serve as a robust prognostic biomarker in ccRCC patients.

LIM domain binding protein 2 (LDB2), a transcriptional co-regulator of the LIM protein family, is reported to be downregulated in various tumors. However, its role in bladder cancer (BLCA) remains undefined. This study analyzed the molecular mechanism of LDB2 in inhibiting the metastasis of bladder cancer and its diagnostic and prognostic value in BLCA. We integrated The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets with enrichment analysis to evaluate the expression, diagnostic potential, and prognostic significance of LDB2 in BLCA. Immunohistochemistry (IHC) was performed to assess LDB2 expression in normal and metastatic tissues and its correlation with clinical stage and prognosis. Functional assays, including clonogenic and Transwell assays, were conducted in LDB2 knockdown and overexpression cell lines to examine its role in proliferation, migration, and invasion. Gene expression was assessed at both mRNA and protein levels using qPCR and Western blot. Additionally, CIBERSORT analysis was performed to explore the correlation between LDB2 expression and immune cell infiltration in BLCA. LDB2 expression was significantly lower in metastatic bladder cancer tissues compared with normal bladder tissues (all p < 0.001). Its expression was positively correlated with early clinical stage and favorable prognosis (all p < 0.05), Moreover, LDB2 showed strong diagnostic performance in distinguishing tumor from normal tissues, with AUC values of 0.91 (95% CI 0.86-0.96) in the TCGA cohort and 0.96 (95% CI 0.88-1.00) in the GSE37815 dataset. Furthermore, in vitro assays demonstrated that LDB2 knockdown significantly promoted invasion, metastasis, and colony formation in bladder cancer cells, whereas its overexpression suppressed these malignant behaviors. Mechanistic studies revealed that LDB2 knockdown markedly reduced the phosphorylation of key MAPK pathway components, including p38 MAPK, ERK1/2, and JNK, whereas LDB2 overexpression enhanced their phosphorylation. Immune infiltration analysis indicated that elevated LDB2 expression was associated with increased immune cell infiltration, particularly showing significant correlations with macrophages and mast cells. LDB2 may serve as a novel diagnostic biomarker and tumor suppressor by inhibiting proliferation, invasion, and metastasis via activation of the p38 MAPK/ERK1/2/JNK pathway and modulating the tumor immune microenvironment.

Cyclooxygenase-2 (COX-2), an enzyme involved in prostaglandin synthesis, was significantly upregulated in various cancers, including esophageal cancer (ESCA). This study investigated the role of COX-2 in cancer progression and its potential as a therapeutic target, utilizing multi-omics approaches, including single-cell RNA sequencing, spatial transcriptomics, protein docking analysis and experimental validation. We found that COX-2 expression was significantly elevated in ESCA and other cancers, correlating with malignant phenotype and poor prognosis. Enrichment analyses revealed that COX-2 was involved in key oncogenic signaling pathways, including TNF/NF-κB and IL-17, which promoted cell proliferation, migration, and invasion. Additionally, COX-2 facilitated a pro-inflammatory microenvironment by enhancing immune cell infiltration, particularly macrophages, monocytes, and mast cells. Functional assays demonstrated that celecoxib, a selective COX-2 inhibitor, effectively reduced ESCA cell proliferation, migration, and invasion in a dose-dependent manner. Pan-cancer analysis confirmed that COX-2 was a poor prognostic indicator across various cancers, highlighting its broader clinical relevance. This study underscored COX-2 as a critical regulator of inflammatory microenvironment and cancer progression in ESCA, supporting its potential as both a prognostic biomarker and therapeutic target. The use of COX-2 inhibitors, such as celecoxib, holds promise for improving patient outcomes in ESCA and other COX-2-associated cancers.

Long non-coding RNAs (lncRNA) participate in regulation of gene expression and biology manipulation and altered lncRNA expression associated with cancer development and progression. The lncRNA SCAMP1 expression was aberrant and changed various cancer malignant behaviors. This study assessed SCAMP1 expression in pancreatic ductal adenocarcinoma (PDAC) for association with clinicopathological parameters and survival of patients and then explored the underlying molecular events. The data revealed that SCAMP1 expression was significantly upregulated in PDAC tissues, which was associated with a larger tumor size and tumor de-differentiation as well as poor survival of patients. Knockdown of SCAMP1 expression reduced tumor cell growth, invasion, epithelial‑mesenchymal transition (EMT), and improved sensitivity to 5-fluorouracil (5-FU) in vitro and inhibited tumor cell xenograft growth in nude mice. At gene levels, SCAMP1 was able to target miR-106a-5p to in turn upregulate acylglycerol kinase (AGK) expression and promote PDAC malignant behaviors in vitro. The data from the current study demonstrated an oncogenic SCAMP1 activity in PDAC. Further study will investigate SCAMP1 as a tumor biomarker and novel target in control of PDAC clinically.