Esophageal cancer is a highly prevalent malignancy worldwide. Although immunotherapy, particularly programmed cell death‑1/programmed cell death ligand 1 (PD‑1/PD‑L1) inhibitors, has notably improved patient outcomes, the overall response rate remains limited. This limited efficacy is largely attributed to complex immunosuppressive networks within the tumor microenvironment (TME). The present review systematically dissects the multifaceted regulatory mechanisms of the PD‑1/PD‑L1 signaling axis in the TME of esophageal squamous cell carcinoma (ESCC), and its impact on immunotherapeutic efficacy. Emerging evidence indicates that multiple immunosuppressive mechanisms within the TME shape the response to immune checkpoint inhibitors: Regulatory T cells enhance immunosuppression via the TGF‑β‑PD‑1/PD‑L1 axis; IL‑6/STAT3 signaling upregulates PD‑L1 expression and mitochondrial remodeling and amino acid network regulation exacerbate T cell exhaustion. Meanwhile, tertiary lymphoid structure (TLS) maturation is positively associated with clinical prognosis by promoting tissue‑resident memory T cell activation and enhancing antitumor immunity. By contrast, the predictive value of tumor mutational burden (TMB) is constrained by TME heterogeneity. Emerging strategies highlight the predictive potential of TLS maturity and TMB, although the predictive relevance of TMB in ESCC remains inconsistent. Combination approaches show promise in reversing T/natural killer cell exhaustion and remodeling immunosuppressive TMEs. Future research should combine multi‑omics data with clinical information to develop personalized immunotherapy models for ESCC.

Melanoma, a highly malignant form of skin cancer, poses significant challenges in oncology due to its aggressive nature and resistance to conventional therapies. Epigenetic modifications, especially acetylation, have emerged as critical regulators of gene expression that influence the pathogenesis and progression of melanoma. Acetylation is a novel post‑translational modification that involves the addition of an acetyl group to lysine residues both in histone and in non‑histone proteins. In the context of melanoma, acetylation has been shown to occupy a pivotal role in regulating cellular proliferation, autophagy, apoptosis and metastasis, as well as drug resistance. The identification of acetylation‑associated biomarkers and therapeutic targets in melanoma is currently an active area of research. The present review aims to elucidate the roles of acetylation modifications in melanoma, and to explore the potential of targeting these modifications for novel therapeutic interventions, with a unique perspective on the acetylation networks mediating therapy resistance.

Pancreatic cancer is characterized by short survival and poor treatment outcomes. Astragaloside IV (AST‑IV), the primary pharmacological component of Astragalus membranaceus, is a traditional Chinese medicinal component with demonstrated anticancer potential. The present study aimed to evaluate the therapeutic efficacy of AST‑IV against pancreatic cancer cells in vitro and to elucidate its underlying mechanisms of action, thereby providing novel insights for its clinical application in the treatment of pancreatic cancer. The effects of AST‑IV on PANC‑1 pancreatic cancer cell viability and migration were assessed using Cell Counting Kit‑8 and wound healing assays, respectively. Subsequently, RNA‑sequencing (RNA‑seq) analysis was performed, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to investigate the mechanisms underlying the effects of AST‑IV. Finally, western blotting experiments were conducted to validate the potential molecular mechanisms of AST‑IV. The results revealed that AST‑IV effectively suppressed the proliferation and migration of the pancreatic cancer cells. In addition, GO and KEGG analyses of the differentially expressed genes identified by RNA‑seq analysis suggested that AST‑IV induced endoplasmic reticulum (ER) stress and influenced critical cellular processes, including cell cycle regulation and DNA damage repair. Furthermore, western blotting demonstrated that AST‑IV significantly activated the protein kinase R‑like endoplasmic reticulum kinase (PERK) signaling pathway, upregulated activating transcription factor 4 expression and induced the overexpression of CCAAT/enhancer‑binding protein homologous protein, indicating that it triggered apoptosis. In summary, these findings suggest that AST‑IV induced apoptosis in pancreatic cancer cells through PERK‑mediated ER stress. These results expand the potential therapeutic applications of AST‑IV and provide a theoretical foundation for the development of novel treatment strategies and therapeutic targets for pancreatic cancer treatment.

Leukemia is a group of hematologic malignancies characterized by the uncontrolled proliferation of abnormal white blood cells, posing significant challenges for diagnosis and treatment because of its complex etiology. Both genetic and environmental factors contribute to leukemogenesis, with recent research highlighting the critical role of epigenetic modifications, particularly histone acetylation and deacetylation, in regulating gene expression and disease progression. Dysregulation of histone deacetylases (HDACs) is frequently observed in leukemia and is correlated with poor prognosis and resistance to conventional therapies. This observation has led to the development of epigenetic drugs for leukemia treatment. The emergence of HDAC inhibitors (HDACis) as targeted therapeutics offers promising avenues for more selective and effective leukemia treatments. The present review covers basic aspects of histone modification and its role in leukemogenesis and evaluates the potential of peptide‑based HDACis as novel drugs for leukemia therapy.

Biliary tract cancer (BTC) encompasses a group of aggressive malignancies arising from the bile duct epithelium, including gallbladder cancer and cholangiocarcinoma, which are characterized by aggressive progression, frequent metastases and poor prognoses. BTC accounts for ~3% of all digestive system tumors, with a 5‑year overall survival rate of <20%. BTC presents a clinical challenge. Despite multidisciplinary therapeutic approaches incorporating surgery, chemotherapy and radiotherapy, persistent obstacles, including high tumor recurrence rates (>50%) and the development of treatment resistance remains, underscoring the urgent need for novel treatment strategies such as targeted therapies and immunotherapies. Ferroptosis, a distinct mechanism of regulated cell death triggered by lipid peroxidation, serves critical roles in disease occurrence and progression. Increasing evidence supports the potential of ferroptosis as a targeted therapy in malignancies, with emerging implications for personalized BTC treatment. The present review investigated the molecular mechanisms and signaling pathways that govern ferroptosis, the advances in the understanding of ferroptosis during the initiation and progression of BTC, and the translation potential of ferroptosis for precision therapeutics. By integrating current knowledge, the present study aimed to provide theoretical suggestions for future mechanistic investigations and clinical studies of ferroptosis‑based interventions for patients with BTC.

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that certain of the westen blot data included in Fig. 4C and D looked strikingly similar, such that the same data may have been included more than once in these figure parts to show the results of differently performed experiments. Upon performing an independent analysis of the data in the Editorial Office, it also came to light that data featured in Fig. 3A of the above paper had been re‑used in a figure in a paper featuring some of the same authors that was published in the journal Scientific Reports. The authors were contacted by the Editorial Office to offer an explanation for this possible anomaly in the presentation of the data in this paper, although up to this time, no response from them has been forthcoming. Owing to the fact that the Editorial Office has been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of this potential problem while the Editorial Office continues to investigate this matter further. [International Journal of Oncology 48: 1985‑1996, 2016; DOI: 10.3892/ijo.2016.3404].

During malignancy, metabolic reprogramming is critical for cancer cells to survive and thrive in nutrient- and oxygen-poor conditions. Autophagy is a catabolic process through which intracellular components are degraded to support cells upon exposure to stressful conditions. While autophagy is protective during early cancer initiation, tumor cells may initiate cell-intrinsic and cell-extrinsic autophagy to support their survival in later stages of cancer. As autophagy is present at low levels in most tissues under homeostasis and upregulated in malignancy, there has been great interest in targeting the autophagy pathway for cancer therapy. Here, we discuss the mechanisms through which autophagy and autophagy-related proteins act to limit carcinogenesis. We then review pro-tumor roles for autophagy in tumor cells as well as in components of the tumor microenvironment. Finally, we discuss autophagy-targeted approaches for cancer therapy. This review article highlights autophagy as a key player in cell metabolism that is often leveraged to support cancer progression and as a potential therapeutic target in a variety of cancer types.

WD Repeat Domain 4 (WDR4) is integral to the development and progression of various cancers; however, its specific role and underlying molecular mechanisms in glioma remain inadequately elucidated. This study undertook an analysis of WDR4 expression levels in glioma and normal brain tissues utilizing publicly accessible datasets from TCGA and GTEx project, with further validation conducted through the GEPIA and the HPA databases. Prognostic significance was assessed using Kaplan-Meier survival analysis and multivariate Cox regression models. Cellular functions were investigated through CCK-8 viability assays, colony formation assays, and cell cycle analysis, while the tumorigenic potential in vivo was corroborated using a nude mouse xenograft model. The findings revealed a significant upregulation of WDR4 in both glioma tissues and cell lines. Elevated WDR4 expression correlated with reduced overall survival and emerged as an independent prognostic factor. Functional assays indicated that WDR4 silencing markedly inhibited glioma cell proliferation, induced G1 phase cell cycle arrest, and resulted in the downregulation of CDK1 and CDK2 protein expression. Further co-expression analysis, GSEA, KEGG pathway enrichment, and western blotting suggested that WDR4 may exert its oncogenic effects through activation of the PI3K/Akt signaling pathway. In conclusion, WDR4 is highly expressed in glioma and promotes tumor progression via the PI3K/Akt-CDK1/2 signaling axis. These findings indicate that WDR4 may serve as a potential prognostic biomarker and therapeutic target in glioma.

Accumulating evidence highlights the critical roles of autophagy-dependent ferroptosis mediators in colorectal cancer (CRC) pathogenesis. To elucidate SIRT6's tumor-suppressive role, HT29 cells stably overexpressing SIRT6 (Oe-SIRT6) were generated via plasmid transfection. Functional assays were performed to evaluate autophagy and ferroptosis. Rescue experiments using the autophagy inhibitor 3-MA or the mTOR agonist MHY1485 were conducted. Quantitative analyses revealed marked downregulation of SIRT6 expression in CRC cell lines (SW620, SW480, and HT29) compared to normal colon epithelial cells. SIRT6 overexpression induced autophagy and activated ferroptosis. The autophagy inhibitor 3-MA blocked SIRT6-driven ferroptosis, which confirmed its dependency on autophagy. Moreover, SIRT6 was found to inactivate mTOR/STAT3 signaling, whereas the mTOR agonist MHY1485 reversed SIRT6 overexpression on autophagy-dependent ferroptosis of CRC cells. Our findings establish SIRT6 as a dual-phase regulator of CRC cell death, suppressing mTOR/STAT3 signaling to orchestrate autophagy-dependent ferroptosis.

Background: Colorectal cancer (CRC) is a leading cause of cancer mortality globally. The molecular mechanisms of CRC and the accumulating immune cell infiltration in the tumor microenvironment (TME) are essential for enhancing the treatment strategy and evaluation of the prognosis. In this study, the authors applied machine learning techniques to single-cell RNA sequencing data to investigate the gene expression characteristics of immune cells in CRC and their association with immune cell infiltration. Methods: Differentially expressed genes (DEGs) in CRC were identified by machine learning methods, including clustering analysis, survival analysis, and gene enrichment analysis, and prognostic models were constructed. CIBERSORT and ESTIMATE algorithms were used to evaluate the abundance of infiltrating immune cells and UMAP and t-SNE techniques were used for dimensionality reduction and visualization of the data. Results: Specific gene expression patterns are closely related to immune cell infiltration in CRC patients. Clustering analysis demonstrated two unique subgroups in the CRC samples, characterized by significant differences in survival outcomes (p = 0.049). These DEGs are enriched in various biological processes, according to gene enrichment analysis. The prognostic models of the receiver operating characteristic curves had good predictive accuracy, with area under the curve values. Single-cell data analysis also showed the intricate associations of immune cells with tumor cells in the TME. Conclusions: This study reveals the complex relationship between gene expression and immune infiltration in CRC using machine learning techniques, and establishes prognostic models with potential value in the clinic. These findings reveal the new potential biomarkers for CRC desensitization and immunotherapy.

Glucokinase regulatory protein (GCKR) is a metabolic regulator implicated in glucose homeostasis, but its genetic and functional roles in cancer remain poorly understood. Through integrated pan-cancer multiomics and experimental analyses, we mapped the expression and mutational landscape of GCKR with a focus on gastric cancer. GCKR expression was downregulated in most tumors but upregulated in subsets such as kidney renal papillary carcinoma (KIRP) and lung adenocarcinoma (LUAD). Genomic profiling revealed recurrent alterations, with the highest mutation frequencies observed in sarcoma (SARC) and uterine corpus endometrial carcinoma (UCEC), and missense mutations representing the predominant variant type, particularly in breast cancer (BRCA). Functionally, reduced GCKR expression in gastric cancer was associated with an immune-cold phenotype characterized by diminished cytotoxic T cell infiltration, impaired antigen presentation, and metabolic reprogramming. Spatial transcriptomics and single-cell analyses highlighted compartment-specific heterogeneity and links with cancer-associated fibroblasts and macrophages. Clinically, low GCKR expression predicted poorer survival and reduced immunotherapy benefit, while higher expression indicated selective sensitivity to MEK inhibitors including refametinib and PD0325901. These findings define GCKR as both a mutation- and expression-driven biomarker that connects metabolic regulation with immune remodeling, offering translational value for prognosis and precision therapy in gastric cancer.

Head and neck squamous cell carcinoma (HNSCC) ranks second among men and sixth globally, with a notable increase in HPV-associated cases. However, the molecular underpinnings and immune landscape of HPV+ HNSCC remain incompletely understood. In this study, we first retrieved and harmonized single-cell RNA sequencing (RNA-Seq), bulk RNA-Seq, and spatial transcriptomic profiles from public repositories. We then applied high-dimensional weighted gene coexpression network analysis (hdWGCNA) and gene nonnegative matrix factorization (GeneNMF) to dissect HPV+ epithelial subpopulations, their extracellular matrix (ECM)-interacting ligand programs, and CXCL/complement immune circuits. Furthermore, we mapped the spatial niches of malignant and immune cells and constructed a consensus prognostic index using 101 machine learning algorithms. Our findings revealed transcriptionally distinct HPV+ epithelial clusters that activate viral oncogenesis, inflammatory pathways, and ECM-sensing pathways. These cells communicate with stromal and immune compartments via CXCL axes and complement cascades, yet they are spatially segregated from lymphocytes. A high-risk signature, identified as HPV-related risk genes including TRMT112, stratified the TCGA-HNSC and GSE65858 cohorts into patients with markedly worse 1-, 2-, and 3-year survival rates (ROC-AUC 0.934, 0.968, and 0.973) and poor responses to immunotherapy. Notably, TRMT112 expression inversely correlated with cytotoxic T-cell infiltration, mechanistically linking it to the formation of "cold" tumors. Our integrative analysis defines HPV-driven epithelial subpopulations whose TRMT112-enriched, immune-excluded microenvironment contributes to therapeutic resistance, thus providing robust prognostic biomarkers and actionable targets for precision immunotherapy in HPV+ HNSCC.

Pancreatic cancer (PC) is characterized by an exceptionally poor prognosis, primarily attributable to its aggressive metastatic behavior and high recurrence rates. Liver metastasis is the predominant distant metastasis model of PC. Moreover, invasion and metastasis of PC are closely associated with the remodeling or loss of basement membrane (BM). Consequently, identifying pivotal genes involved in PC liver metastasis (PCLM) and BM could pave the way for more effective and precise targeted therapies. This study aims to construct a prognostic model based on PCLM and BM-related genes, while also validating the association between this model and the immune microenvironment of PC, as well as its predictive value for the efficacy of chemotherapy and immunotherapy.

Cisplatin resistance is a major challenge in ovarian cancer therapy, particularly for high-grade serous ovarian cancer (HGSOC). DNA topoisomerase IIα (TOP2A) relates to cancer drug resistance, yet its role and molecular mechanisms in ovarian cancer cisplatin resistance remain unclear.

Oral squamous cell carcinoma, with high global incidence and mortality, requires improved early intervention strategies. Ubiquitination - a critical post-translational modification - has been strongly implicated in tumorigenesis, with particularly significant roles in T-cell regulation. We developed a T Cell-Related ubiquitination risk model that enhances prognostic prediction and immunotherapy response assessment, offering a framework for personalized OSCC manageme.

Breast cancer persists as a principal contributor to global cancer mortality, driven by heterogeneous molecular pathways. Necrosis by sodium overload, a recently characterized form of regulated cell death, remains underexplored in oncogenesis. This study investigates the pathobiological significance and therapeutic potential of NECSO-related genes in breast cancer, elucidating their mechanistic roles in tumor progression.

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide, characterized by increasing incidence rates and challenging prognoses. This study integrates single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics to unravel the complex molecular and structural landscape of HCC, focusing on the identification of mitochondrial-related genes (MitRGs) and their pivotal role in disease progression. Utilizing scRNA-seq and bulk RNA-seq data, we performed a comprehensive differential expression analysis to highlight MitRGs. A modeling approach using 92 combinations of nine machine learning algorithms was applied, producing a predictive model with good performance. Among the genes analyzed, FLAD1 emerged as significantly upregulated in HCC tissues, correlating with advanced disease stages and poorer patient outcomes, and exhibited exceptional diagnostic accuracy with an AUC of 0.962. Functional enrichment analyses revealed that high FLAD1 expression is involved in crucial biological processes like copper ion detoxification and heme complex assembly. Interaction networks further elucidated the connection between FLAD1 and critical HCC pathways, with its expression levels negatively correlated with key immune effector cells such as CD8+ T cells and DCs. Spatial transcriptomics analysis provided a structural basis for this immune exclusion, demonstrating that an intact tumor capsule can function as a physical barrier that fosters an immune-exempt microenvironment. This analysis also validated FLAD1 upregulation within the spatial context of the tumor. Additionally, DNA methylation analysis indicated a hypomethylation pattern in the FLAD1 promoter region, likely contributing to its overexpression in HCC. Validation of FLAD1 protein levels in an in-house cohort via Western blotting further confirmed these findings. Collectively, our integrative study highlights the utility of MitRGs as potential biomarkers and positions FLAD1 as a dual prognostic and therapeutic target linked to the structural and immune landscape of HCC.

Glioblastoma (GBM) exhibits marked plasticity and intense microenvironmental crosstalk. We aimed to delineate mesenchymal programs with spatial resolution, clinical relevance, and mechanistic anchors.

The international Phase 3 LAURA trial (NCT03521154) demonstrated that the use of osimertinib following chemoradiotherapy markedly improved survival outcomes in unresectable stage III NSCLC with epidermal growth factor receptor (EGFR) mutations. Considering the high cost of targeted therapy, the popularization of osimertinib in clinical practice should be considered comprehensively in terms of cost and efficacy. This study was to investigate the cost-effectiveness of osimertinib for unresectable stage III EGFR-mutated NSCLC without disease progression after chemoradiotherapy from the perspective of payers in the USA and China.

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Isocitrate dehydrogenase (IDH) is a key enzyme in the tricarboxylic acid cycle and one of the common mutated genes in AML. Although the 2022 version of the ELN guidelines suggests that IDH mutations cannot be used as a separate prognostic stratification indicator, multiple studies have indicated that IDH mutations have prognostic significance for AML. Early identification of IDH mutations and selection of appropriate treatment options are crucial. This review summarizes the research progress on the characteristics, carcinogenic mechanisms, prognosis of IDH mutations in AML patients, and treatment options, in order to provide reference for further improving the prognosis of IDH -mutated AML patients.