Correlation of lymphocytic infiltration and degree of pleomorphism with tumor mutation burden in high-grade urothelial carcinoma.

Pitfalls in MLH1 promoter methylation assessment, including POLEmut/MLH1meth endometrial adenocarcinoma.

zDHHC-mediated palmitoylation modification patterns and tumor immune microenvironment infiltration characterization in pancreatic cancer.

Loss of Ribosomal Protein L22 (RPL22) Expression Identifies a Transcriptional Subset of MLH1-Deficient Endometrial Cancers With Lower Numbers of Tumor-Associated Lymphocytes.

Immunopeptidomics combined with full-length transcriptomics uncovers diverse neoantigens.

Hpv-driven rewiring of the tumor immune microenvironment through single-cell profiling informs prognosis and therapy in HNSCC.

BAG6 promotes hepatocellular carcinoma growth via enhancing PLK1-mediated aerobic glycolysis.

Integrated multi-Omics and network toxicology elucidate the multi-target mechanisms of environmental hormones in driving hepatocellular carcinoma.

The role of therapeutic cancer vaccines in the modern immunotherapy era: state of the art with recent progress and future challenges.

Mutational Signature in Cancers Following Solid Organ or Allogeneic Stem Cell Transplantation.

Immune escape in colorectal cancer: Mechanisms and challenges of immune checkpoint inhibitor resistance.

Background: Pancreatic adenocarcinoma (PAAD), often referred to as the “king of cancers,” remains poorly understood in terms of the regulatory mechanisms involving brown adipocytes (BAs). Methods: Bioinformatics approaches were employed to explore the role of BAs in PAAD progression, utilizing transcriptomic data from public databases. Prognostic genes were identified through differential expression analysis, univariate Cox regression, and machine learning. A risk model categorizing patients into high- and low-risk groups was developed, accompanied by a nomogram. Functional analysis, immune microenvironment profiling, somatic mutation analysis, and drug sensitivity testing were performed, with further validation via gene localization, immunohistochemistry, and clinical sample analysis. Results: Six prognostic genes (SERPINB5, CALU, TFRC, LY6D, SFRP1, and GBP2) were identified, with the model and nomogram exhibiting robust predictive performance. Notable differences between the high- and low-risk groups were found in immune pathways, cell infiltration, tumor mutational burden, and drug sensitivity (e.g., axitinib). Conclusions: SERPINB5, SFRP1, and TFRC were highly expressed in PAAD samples, providing new insights into potential therapeutic strategies in PAAD treatment.

High-grade serous ovarian cancer (HGSOC) exhibits poor prognosis due to late diagnosis, chemoresistance, and limited responses to immune checkpoint inhibitors. Although tumor-infiltrating CD8+ T cells correlate with improved survival, current prognostic models remain inadequate. Thus, robust biomarkers linked to CD8+ T cell activation are urgently needed to guide clinical management. Transcriptomic and clinical profiles from 874 late-stage HGSOC patients were analyzed via single-sample gene set enrichment analysis for immune infiltration and weighted gene co-expression network analysis to identify CD8+ T cell-associated genes. An integrative machine learning approach was employed to develop a CD8⁺ T cell-associated immune prognostic signature (CIPS), which was then validated across multiple independent cohorts and benchmarked against 56 published models. CIPS was further characterized using single-cell RNA-seq analysis. The resulting 10-gene signature independently predicted overall survival in all cohorts and consistently surpassed most clinicopathological variables and comparator models. Low-risk patients exhibited significantly enhanced CD8+ T cell and cytotoxic gene scores, correlating with better responses to chemotherapy and immunotherapy. CIPS inversely correlated with tumor-mutation burden, BRCA1/2 mutations and homologous-recombination deficiency. Single-cell analysis localized signature genes to T lymphocyte and myeloid compartments and linked elevated CIPS activity to augmented intercellular communication in platinum-resistant tumors. CIPS captures a CD8+ T cell activation program that powerfully stratifies late-stage HGSOC, forecasts therapeutic benefit and offers a practicable biomarker for personalized immuno-oncology strategies.

DDB1 and CUL4-associated factor 7 (DCAF7) is a WD-repeat adaptor that recruits substrates to the CUL4DDB1 ubiquitinligase complex, but its pan-cancer relevance and mechanistic contribution to tumor progression remain unclear. Multi-omics datasets (genomic, transcriptomic, epigenomic, proteomic and single-cell) from 33 tumor types were integrated to define DCAF7 expression, regulation, and clinical significance. Somatic alterations and copy-number variation were analysed across cohorts, and promoter methylation and RNA modification signatures were interrogated. Immune associations were assessed by computational deconvolution and checkpoint-gene profiling. Pathway and network analyses were performed to infer DCAF7-linked programmes. Mechanistic and functional validation was conducted in hepatocellular carcinoma (LIHC) cell lines (HepG2, Huh7) using DCAF7 perturbation and pharmacologic Wnt inhibition. DCAF7 was overexpressed in most cancers, consistent with copy-number gain, focal promoter hypomethylation and putative m6A-linked post-transcriptional regulation, whereas hypermethylation at two CpG loci predicted poor prognosis in LIHC. DCAF7 alterations, predominantly amplifications, were associated with shorter overall survival in LIHC and positively correlated with DCAF7 mRNA abundance across cohorts. Immunogenomic analyses linked high DCAF7 to CD4+ T-cell enrichment, broad upregulation of checkpoint genes (PD-1/PD-L1, CTLA-4, TIGIT), and increased tumour mutational burden, microsatellite instability and neoantigen load, suggesting an immune-evasive phenotype. Network and enrichment analyses converged on canonical Wnt/β-catenin, Hippo and cell-cycle programs. In vitro, DCAF7 promoted LIHC cell proliferation and migration by stabilising β-catenin via increased inhibitory Ser9 phosphorylation of GSK-3β, thereby inducing c-Myc and cyclin D1; DCAF7 knockdown or the Wnt inhibitor XAV939 attenuated these effects. Drug-response modelling further predicted increased sensitivity of DCAF7-high tumours to 17-AAG, docetaxel and alsterpaullone. DCAF7 is frequently activated by genetic and epigenetic mechanisms across cancers, associates with an immunotherapy-relevant tumour immune milieu, and drives Wnt/β-catenindependent malignant phenotypes in LIHC. These findings support DCAF7 as a prognostic biomarker and a candidate therapeutic target, particularly for stratified intervention in LIHC. DCAF7 is up-regulated in various tumours and correlates with poor prognosis, particularly in LIHC. High DCAF7 expression is linked to CD4+ T cell infiltration, up-regulation of immune checkpoint genes and increased tumour mutational burden, suggesting a role in tumour immune escape. DCAF7 stabilises β-catenin by enhancing GSK-3β Ser9 phosphorylation, thereby driving c-Myc/cyclin D1 expression and contributing to proliferation and migration in LIHC. DCAF7-high tumours demonstrate therapeutic vulnerability to 17-AAG, docetaxel and CDK/GSK-3 inhibitor, revealing potential targeted treatment strategies.

Breast cancer (BRCA)'s molecular heterogeneity complicates prognosis and treatment. Tumor Doubling Time (TDT), a critical growth rate metric with clinical and prognostic significance, offers untapped potential as a biomarker to decode heterogeneity and improve therapeutic strategies. Based on transcriptomic and clinical data from TCGA and GEO, this study analyzed BRCA. Through differential expression and survival analyses, differentially expressed tumor doubling time-related genes (TDTRGs) with prognostic significance were identified. Consensus clustering using these genes defined two molecular subtypes. A prognostic risk model was constructed and validated through LASSO and multivariate Cox regression. Comprehensive evaluation was performed on these molecular subtypes and risk groups, encompassing immune infiltration (ssGSEA, CIBERSORT, ESTIMATE), mutational burden, response to immunotherapy (IMvigor210), and drug sensitivity (CellMiner, pRRophetic). This study constructed and validated an 8 gene prognostic risk model demonstrating robust predictive performance in both training (AUCs: 1-year=0.703, 3-year=0.693, 5-year=0.671) and validation cohorts. The low-risk group showed significantly enhanced immune cell infiltration, elevated immune checkpoint expression, and improved response to immunotherapy. Conversely, the high-risk group displayed increased tumor purity, metabolic reprogramming (e.g., respiratory electron transport), genomic instability, higher tumor mutational burden, and differential drug sensitivity (e.g., resistance to Gemcitabine/Tamoxifen). This study establishes a novel TDTRGs framework for BRCA molecular classification and validated prognostic stratification. It reveals key disparities in immune microenvironment and genomic stability, enhancing understanding and guiding personalized therapeutic strategies.

Inflammation plays a critical role in cancer initiation and progression by modulating the tumor microenvironment and immune responses. Interleukin-1 receptor-associated kinase 2 (IRAK2) is a key mediator of the Toll-like receptor and interleukin-1 receptor signaling pathways, its pan-cancer expression patterns, genomic and epigenetic features, immune-related roles, and clinical relevance remain unclear. The expression patterns of IRAK2 across multiple cancer types, transcript variants, single-cell distribution, prognostic significance, and biological functions were comprehensively evaluated through analyses of multiple databases and multi-dimensional datasets. Furthermore, the correlations of IRAK2 with the immune microenvironment, epigenetic modifications, and drug sensitivity were investigated. The potential role of IRAK2 in hepatocellular carcinoma was further explored through both in vitro and in vivo experiments. Aberrant expression of IRAK2 was observed in the majority of cancer types, with a relatively high proportion of expression detected in macrophages, and was found to be associated with the prognosis of certain cancers. In most cancer types, IRAK2 expression showed significant correlations with immune cell infiltration, the cancer-immunity cycle, major histocompatibility complex molecules, immune checkpoints, tumor mutational burden, microsatellite instability, RNA modifications (including m1A, m5C, and m6A), and DNA methylation sites. Both in vitro and in vivo experiments demonstrated that knockdown of IRAK2 markedly reduced the proliferative capacity of hepatocellular carcinoma cells. The present study highlights the potential of IRAK2 expression as a novel biomarker for predicting the prognosis and immunotherapeutic response across various human cancers.

Background/Objectives: PHF6 is a chromatin-binding protein located in the nucleus, and it is involved in transcriptional regulation. However, limited research exists on the specific roles and mechanisms of PHF6 across various tumors. Methods: Based on The Cancer Genome Atlas (TCGA) database, we analyzed PHF6 expression in pan-cancer. We first evaluated the relevance between PHF6 and prognosis; then, the relevance between PHF6 and immune cell infiltration in pan-cancer were analyzed. Subsequently, we explored the correlation between PHF6 and cancer heterogeneity, such as tumor mutation burden (TMB) and microsatellite instability (MSI), as well as cancer stemness. Finally, the role of PHF6 was validated in liver cancer and pancreatic cancer cell lines by cell proliferation assays. Results: PHF6 expression was higher in the vast majority of cancers than their normal counterparts. PHF6 was substantially correlated with prognosis and immune cell infiltration in various cancers. Moreover, PHF6 expression showed a strong correlation with cancer heterogeneity and stemness in certain cancer types. Additionally, the depletion of PHF6 inhibited cell proliferation in both liver and pancreatic cancer cells. Conclusions: PHF6 expression was closely associated with the occurrence and development of many types of cancer, and it might promote cancer progression by inhibiting the function of the immune microenvironment, while knockout of PHF6 significantly inhibited the tumor cells proliferation.

ABSTRACT This study investigated mitochondrial permeability transition-driven necrosis-related genes (MPTDNRGs) and its association with lung adenocarcinoma (LUAD). We systematically investigated their genetic variation, expression patterns, and prognostic value. A risk prediction model for MPTDNRGs was contrasted using Cox regression and least absolute shrinkage and selection operator regression analyses. MPTDNRG scores were used to quantify LUAD subtypes. We evaluated their value in the tumor microenvironment (TME), tumor mutational burden (TMB), prognostic prediction, and drug sensitivity in LUAD. The expression level, copy number variation, methylation, and microRNA (miRNA) status of PSMB7 were analyzed. We also analyzed the expression and knockdown efficiency of PSMB7 in LUAD by immunohistochemical staining, real-time fluorescence quantitative polymerase chain reaction, and western blotting. PSMB7 function in LUAD cells and in vivo was assayed using Cell Counting Kit 8, colony formation, wound healing, Transwell assays, flow cytometry, and mouse models. Seven MPTDNRG features were successfully constructed to predict LUAD prognosis and validated in an external cohort. Patients were categorized into high- and low-risk groups based on risk scores. The high-risk group exhibited shorter survival times, lower TME scores, weaker TME cell infiltration, and higher TMB scores than the low-risk group. Cancer stem cell index, mutation frequency, and drug sensitivity significantly differed between the two groups. MPTDNRG score could independently predict LUAD. PSMB7 was highly expressed in various tumors, and copy number variation, methylation, and miRNA expression significantly differed among different cancers. PSMB7 was highly expressed in LUAD tissues and cell lines. PSMB7 knockdown inhibited cancer cell proliferation, migration, invasion, and epithelial – mesenchymal transition, and promoted apoptosis. PSMB7 exerted tumorigenic effects in mice. In conclusion, we comprehensively demonstrated the characterization of MPTDNRGs in LUAD and constructed a new risk prediction model. Meanwhile, PSMB7 was shown to be a possible new target for LUAD treatment.

This study aimed to identify and predict bioactive small molecules and immunogenic antigen epitopes targeting proteins with point mutations in colitis-associated colorectal cancer (CAC), using integrative bioinformatics approaches. Genes associated with colorectal cancer (CRC), ulcerative colitis (UC), diabetes mellitus (DM), hyperlipidemia (HL), gout, and functional dyspepsia (FD) were obtained from disease databases and GEO. Overlapping genes were identified using jvenn. CIBERSORT was used for immune infiltration analysis. Prognostic significance was evaluated using KM Plotter, and gene co-expression correlations in CRC were assessed via TIMER. cBioPortal was employed to analyze mutation profiles, tumor mutational burden (TMB), and microsatellite instability (MSI). Allosteric sites were predicted using AlloDriver. Molecular docking (AutoDock Vina v1.2.3) and 100-ns molecular dynamics simulations (GROMACS v2022.03) assessed protein-ligand interactions. Neoantigen and B-cell epitope immunogenicity were predicted using NetMHCpan-4.1 and IEDB, respectively. SERPINE1, SELE, SPP1, PLAU, COL1A1, PTGES, IL6, KDR, and ICAM1 were significantly upregulated in CAC. Lower expression correlated with improved relapse-free and overall survival (log-rank P < 0.05) and was associated with CRC molecular subtypes and biomarkers (P < 0.05). Mutations PLAUY151H, SERPINE1V166A, and KDRP359H were located in allosteric sites. Anacetrapib and LY2090314-metabolism-related compounds-showed high affinity for wild-type KDR, PLAU, and SERPINE1.The KDRP359H and PLAUY151H significantly weakened LY2090314 binding, and SERPINE1V166A mutation significantly reduced Anacetrapib binding, whereas SERPINE1V166A significantly enhanced LY2090314 binding. Although HLA-I affinity of mutation-derived antigens was low, four mutated B-cell epitopes (COL1A1R493H, KDRP551S, ICAM1T1259M, KDRT1260M) exhibited higher immunogenicity than wild-type, suggesting potential for antibody-based therapy. Based on bioinformatics analysis, this study identified nine genes significantly upregulated in CAC and associated with prognosis. Allosteric-site mutations in PLAU, SERPINE1, and KDR affect the binding stability of small-molecule drugs (Anacetrapib, LY2090314), suggesting their role in drug response. Four mutation-specific B-cell epitopes (COL1A1R493H, KDRP551S, ICAM1T1259M, KDRT1260M) exhibit enhanced immunogenicity, indicating potential for antibody-based therapy.

Diffuse midline gliomas, including diffuse intrinsic pontine gliomas, represent one of the most aggressive pediatric malignancies in the central nervous system with a uniformly poor prognosis. They can be consistently identified by mutations in histone H3 K27M, which are associated with aggressive tumor biology, marked resistance to therapies, and abysmal survival. The current review critically assesses the existing application of immunotherapeutic modalities in DMGs, emphasizing biological hurdles in efficacy, translation methodologies, and prospects in attaining sustained responses. We examined preclinical and early clinical studies in DMGs for immune therapies such as peptide vaccines against H3K27M antigens, chimeric antigen receptor T-cell therapies, immune checkpoint modulation, and radioimmunotherapy. Current developments in the interface of cancer neuroscience and tumor interaction with neurons were incorporated in a manner relevant to immune suppression in the microenvironment of DMG. Although these tumors have traditionally shown poor immune reactivity because of low tumor mutational burden, immune-privileged sites, and a strongly suppressive tumor microenvironment, a variety of different immune therapeutic approaches have shown promising early efficacy. Of particular interest are neoantigen-targeted vaccines and CAR T-cell therapy using surface antigens. Preliminary findings suggest an important role for neuron-glioma synaptic and paracrine signaling in mediating tumor progression and immune evasion. Immunotherapy for DMGs is moving from a conceptual state to a translational reality. A better understanding of the realm of tumor immune-neural crosstalk, combination therapies, and immune biology in pediatric patients will be critical in addressing resistance and providing durable control for these aggressive malignancies.