Cancer genomes shape the immune landscape within the tumor microenvironment (TME), thereby influencing host antitumor immunity. Identifying somatic mutations that modulate the TME is critical for selecting patients most likely to benefit from immunotherapy. Here, by integrating a transcriptome-based predictive model with comprehensive genomic analyses, we identified SF3B1 splicing factor mutations associated with the response to immune checkpoint inhibitors (ICIs). We systematically evaluated the effects of SF3B1 mutations on the TME and ICI response through in silico, in vitro, and in vivo approaches. Comparative analyses of patient genotypes, together with loss- and gain-of-function studies, revealed that SF3B1 mutations drive transcriptional reprogramming that enhances ICI responsiveness. To validate these findings in vivo, we established a syngeneic mouse model using immune-resistant B16F10 melanoma cells. SF3B1-mutant tumors, compared with wild-type counterparts, exhibited TME features and immune profiles indicative of an enhanced antitumor immune response, including increased proportions of CD4⁺ and CD8⁺ T cells and dendritic cells, accompanied by the upregulation of immune effectors. Consistently, mice bearing SF3B1-mutant tumors demonstrated significantly greater tumor regression following anti-PD-1 treatment compared with their wild-type counterparts. These findings establish SF3B1 mutations as predictive biomarkers for guiding rational immunotherapy selection in cancer patients.

Autoimmune gastritis (AIG) is a chronic immune-mediated atrophic disease that can induce cancer-related epithelial remodeling, although its association with gastric adenocarcinoma depends on histological and clinical modifiers. Gastric cancer (GC) progression is shaped by the tumor microenvironment (TME), including cancer-associated fibroblasts (CAFs), myeloid cells, and extracellular matrix (ECM) remodeling. Whether AIG-related mucosal remodeling shares stromal programs with GC-associated stromal-myeloid niches remains unclear.

We integrated one AIG bulk-transcriptomic cohort and three GC cohorts to identify shared differentially expressed genes (DEGs), followed by LASSO, random forest and protein-protein interaction (PPI) analyses. TIMP1 was evaluated using tissue transcriptomic cohorts, serum RT-qPCR, survival analysis, immune infiltration profiling, scRNA-seq, inferCNV-based epithelial classification, CellChat ligand-receptor inference and spatial transcriptomics.

A total of 51 shared DEGs were identified between AIG and GC. TIMP1 was the only candidate supported by both machine-learning screening and PPI hub-gene analysis. TIMP1 was upregulated in GC tissues and serum and showed an exploratory tumor-normal ROC AUC of 0.941 in the TCGA_STAD cohort, while higher TIMP1 expression was associated with poorer overall survival. Functional analyses linked TIMP1-high GC to ECM organization, integrin binding, epithelial-mesenchymal transition (EMT), transforming growth factor-β signaling and immune infiltration. scRNA-seq of 160,812 GC cells localized TIMP1 mainly to CAF and myeloid compartments. In AIG, TIMP1-high fibroblasts displayed enhanced CAF-associated stromal and inflammatory transcriptional programs. CellChat and spatial transcriptomics further linked TIMP1-associated stromal and myeloid states to ECM-dominant communication and fibroblast-rich, myeloid-associated remodeling regions.

TIMP1 may mark related stromal-myeloid remodeling states across AIG-associated mucosal remodeling and GC, providing a hypothesis-generating framework potentially relevant to inflammation-associated gastric tumorigenesis.

Heart failure (HF) is clinically associated with aggravated breast cancer (BC) progression; however, the integrative genomic mechanisms underlying this cardio-oncological crosstalk remain poorly understood.

We conducted integrative bioinformatics analyses combining weighted gene co-expression network analysis (WGCNA) and machine learning algorithms to screen key hub genes involved in HF and BC progression. The candidate gene Col10a1 was further validated using myocardial infarction (MI)-induced HF xenograft mouse models, paired clinical plasma and tumor specimens, and comprehensive in vitro functional assays.

COL10A1 expression was higher in breast cancer patients with CVD than in BC-only patients. Given the limited sample size, these findings were considered exploratory. Mechanistically, elevated Col10a1 was associated with activation of the transforming growth factor‑β (Tgf-β)/Smad signaling pathway and induction of epithelial-mesenchymal transition (EMT). In vivo, the HF microenvironment markedly accelerated BC tumor growth and was accompanied by enhanced Col10a1 expression and Tgf-β signaling activation. In vitro, cardiomyocyte-derived Col10a1 significantly promoted the proliferation, migration, and invasion of BC cells, whereas Col10a1 knockdown significantly attenuated these malignant phenotypes.

Our study identifies a potential regulatory link between HF and BC and provides preliminary mechanistic insights into the role of Col10a1 in BC progression under cardiac injury conditions. Col10a1 may serve as a candidate mediator in the interaction between cardiac injury and BC progression.

The management of thyroid cancer has advanced through the integration of molecular imaging, genomic profiling, and bioinformatics, supporting precision oncology across diverse subtypes. Although radioiodine imaging and therapy remain standard for differentiated thyroid cancers, efficacy can be limited in refractory cases due to heterogeneous iodine uptake. Advances including dosimetry-guided radioiodine therapy, hybrid imaging modalities (SPECT/CT, PET/CT, PET/MRI), and novel radiotracers (FDG, NaF) may improve diagnostic accuracy and therapeutic decision-making, particularly for aggressive tumors. Genomic profiling has reshaped tumor classification, prognosis, and therapy selection by identifying key alterations in BRAF, RAS, RET/PTC, PAX8/PPARγ, TERT, TP53, ALK, and NTRK. Targeted inhibitors against BRAF, RET, and NTRK demonstrate clinical benefit, while synergistic mutations such as BRAF V600E with TERT promoter highlight tumor complexity and may support investigation of combination strategies. Recent studies have utilized bioinformatics and multi-omics analyses for high-throughput mutation mapping, pathway analysis, and biomarker discovery, leveraging patient genomic data from TCGA and cBioPortal with visualization via R packages such as ggplot2, dplyr, ggrepel, and tidyr. Pathway analyses using GO, KEGG, and Reactome databases revealed involvement in extracellular matrix organization, cell junction assembly, PI3K-Akt signaling, and collagen formation. Integrating insights from molecular imaging, genomics, and computational biology enhances understanding of tumor biology, supports risk stratification, and informs the design of personalized therapies. Future directions include machine learning-driven data integration and expanded clinical application of next-generation sequencing and hybrid imaging to improve patient stratification and management.

Somatic loss of the Y chromosome (LOY) is the most frequent acquired genomic alteration in aging males and occurs across multiple cancer types. While common, its functional role in tumorigenesis is only beginning to emerge. Most studies treat LOY as a binary event, ignoring partial deletions that may selectively remove gene-rich euchromatic regions. To address this, we used high-coverage whole-genome sequencing, large-scale transcriptomics, and eQTL to map male cancer cell lines, eliminating confounding non-malignant cells. We reveal a region-specific LOY landscape with recurrent euchromatic deletions affecting protein-coding genes and non-coding elements. Losses were quantified using a new Y EroSion (YES) Score, which is associated with transcriptional differences and clinical outcome patterns suggestive of functional relevance. Retained Y-linked loci remain transcriptionally active, enriched for proliferation, immune signaling, and stress adaptation functions. These findings position LOY as a structured genomic event with regulatory and clinical implications, motivating validation in primary tumor cohorts.

Tumor Electric Field Therapy (TEFT) disrupts mitosis in glioblastoma (GBM), but responses vary markedly among patients. In a retrospective cohort of TEFT-treated GBM, EGFR variant III (EGFRvIII) alteration is associated with shorter progression-free survival, prompting us to investigate a genotype-linked resistance mechanism. TEFT triggers a broadly shared bioenergetic stress response marked by activation of the AMPK-PPARα-CPT1A axis, whereas EGFRvIII primes IDO1 transcription through NF-κB. CPT1A further stabilizes IDO1 by promoting succinylation at lysine 377 through non-canonical LSTase-related activity, thereby limiting TRIM21-dependent ubiquitination and proteasomal degradation. Accumulated IDO1 increases kynurenine production and activates AhR, which upregulates DCLK1 and ARHGEF2 to preserve spindle organization and microtubule dynamics during electric-field exposure. Thus, EGFRvIII converts a general stress-adaptation pathway into a selective cytoprotective program. Genetic or pharmacological disruption of this pathway restores TEFT sensitivity in established and patient-derived GBM cells, organoids, and orthotopic models. Osimertinib suppresses the EGFRvIII-NF-κB-IDO1 arm and enhances TEFT efficacy, while exploratory clinical cases provide preliminary mechanism-informed support for the combination in recurrent EGFR-driven GBM. These findings define a genotype-field convergence mechanism linking metabolic adaptation to mitotic protection and support prospective evaluation of osimertinib plus TEFT.

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective targeted therapies. A multitarget gene therapy was developed and validated to overcome molecular heterogeneity and compensatory survival signaling in TNBC. A codon-optimized human transcriptional intermediary factor 1 gamma (opti-hTIF1γ) gene therapy was evaluated in ex vivo-cultured patient biopsy tissues and in orthotopic and mammary intraductal mouse models, and the underlying mechanisms were investigated using pathway and immune-functional analyses. Ex vivo findings were further validated using patient-derived cells and complementary mechanistic studies, including ubiquitination assays, chromatin immunoprecipitation, and functional macrophage coculture analyses, to define the molecular basis of TIF1γ-mediated antitumor activity. Transduction of opti-hTIF1γ to ex vivo-cultured biopsy tissues from TNBC patients suppressed epithelial-to-mesenchymal transition and proliferation while inducing apoptosis. In orthotopic and mammary intraductal mouse models, opti-hTIF1γ effectively suppressed tumor growth and lung metastasis. Mechanistically, opti-hTIF1γ inhibits β-catenin via ubiquitination-dependent degradation and inhibits the SMAD-dependent TGFβ pathway by binding to SMAD2/3. In parallel, it suppresses the SMAD-independent TGFβ pathway via ubiquitination and caspase-3-associated degradation of STAT3, leading to the inhibition of TAK1. Furthermore, opti-hTIF1γ downregulates STAT3-dependent immune modulators such as CD47 and CXCL5 in TNBC, enhancing macrophage phagocytosis. These findings position opti-hTIF1γ as a promising multitarget gene therapeutic strategy for TNBC through concurrent suppression of tumorigenic signaling and reprogramming of the immune landscape.

Acetyl tributyl citrate (ATBC) is an alternative plasticizer to Di(2-ethylhexyl) phthalate (DEHP) and bisphenol A (BPA) that may contribute to the development of various cancers. The cytotoxic activity and pro-tumorigenic role of ATBC in prostate cancer (PCa) progression remains poorly understood, highlighting the need for a systematic evaluation of its molecular toxicity.

This study identified potential targets of ATBC in PCa by integrating multiple online databases, including GEO, ChEMBL, STITCH, and Swiss Target Prediction. Protein-protein interaction (PPI) analysis was performed on the intersecting targets, followed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment, and immune microenvironment analyses. Subsequent these crucial targets were identified through the application of machine learning algorithms, specifically the Support Vector Machine-Recursive Feature Elimination (SVM-RFE) and Least Absolute Shrinkage and Selection Operator (LASSO). The expression of these targets was validated using external datasets from The Cancer Genome Atlas (TCGA) and in vitro experiments. Molecular docking analysis was used to explore the interactions between the key genes and ATBC. Finally, virtual knockout and pathway enrichment analysis simulations on single-cell RNA-seq data were conducted to investigate the biological functions of these genes.

Through the utilization of multiple online databases, we identified 45 potential targets associated with ATBC exposure-related PCa. Further refinement using STRING and Cytoscape software elucidated the PPI network. GO and KEGG pathway analyses revealed that these targets, associated with ATBC and PCa, were predominantly enriched in several signal pathways. Subsequent analysis employing machine learning algorithms identified three core targets: EZH2, DNMT1, and PRMT5, which influence the immune infiltration of PCa. Additionally, molecular docking analysis and in vitro experiments further confirmed these potential therapeutic targets. Virtual knockdown of DNMT1, EZH2, and PRMT5 reveals their essential role in preserving collagen-rich ECM integrity and cell-matrix adhesion to maintain prostatic stromal homeostasis, whose disruption mediates ATBC-induced cytotoxicity and potential pro-tumorigenic effects.

Overall, the findings provide new insights into linking the effects of ATBC to PCa, and they provide a preventive and therapeutic strategy for PCa that exposure to the environments with excessive ATBC levels.

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents and is characterized by high aggressiveness and poor prognosis. Although surgery and chemotherapy have improved overall survival, outcomes for relapsed or metastatic disease remain extremely poor, thus underscoring the urgent need for novel therapeutic strategies. Natural killer (NK) cells are key cytotoxic effectors in tumor immunity, but their function is profoundly suppressed within the OS tumor microenvironment. Furthermore, the role of cancer-associated fibroblasts (CAFs) in mediating NK-cell dysfunction through metabolic regulation remains insufficiently understood. We established coculture systems of NK cells, OS cells, and CAFs and assessed NK-cell activation and cytotoxicity by using functional assays, flow cytometry, and immunofluorescence. Metabolic profiling was performed with extracellular acidification rate, oxygen consumption rate, reactive oxygen species detection, MitoTracker staining, and electron microscopy. Integrated proteomics and mechanistic studies were used to identify CAF-derived metabolites and their effects on NK-cell metabolism. CAFs markedly impaired NK-cell recognition and cytotoxicity toward OS cells, accompanied by metabolic reprogramming characterized by enhanced glycolysis, increased reactive oxygen species production, and reduced mitochondrial activity. Multiomics and functional analyses identified β-hydroxybutyrate (BHB) as a key CAF-derived metabolite that contributed to reduced NK-cell FAO and effector function. BHB treatment increased FXR1 Kbhb and reduced FAO, cytokine secretion, and tumor-cell killing, whereas FXR1 K56 mutation attenuated these functional changes. In vivo, CAF-CM treatment was accompanied by elevated circulating BHB, reduced NK-cell activation, and accelerated tumor growth. Targeting the CAF-BHB- FXR1 axis may represent a promising therapeutic strategy to restore NK cell-mediated antitumor immunity and improve treatment outcomes.

Ubiquitination and deubiquitination play critical roles in gastric cancer progression, yet systematic investigations of ubiquitin-regulating proteins in gastric cancer (GC) remain limited. To identify key regulators, we performed Ubiquitin-Focused CRISPR-Cas9 growth-based screening in GC cells and identified the deubiquitinase OTUD4 as a candidate gene promoting tumor growth. Functionally, OTUD4 was found to act as an oncogene by promoting the proliferation and metastasis of GC cell. Mechanistically, OTUD4 interacts with FXR1 through its N-terminal region (1-245 aa), and mutation of the catalytic cysteine residue (C45A) markedly impairs this interaction. OTUD4-mediated deubiquitination removes K48-linked polyubiquitin chains from FXR1, thereby protecting FXR1 from proteasomal degradation and increasing its stability. The resulting accumulation of FXR1 enhances HIF1A mRNA stability, leading to increased HIF1A expression. Consequently, HIF1A activates glycolytic programs and promotes the malignant progression of gastric cancer. Clinically, OTUD4 expression was significantly higher in tumor tissues, and higher OTUD4 levels were linked to decreased overall survival. Importantly, OTUD4 and FXR1 expression levels show a positive correlation in human GC samples. Collectively, these findings uncover an OTUD4-FXR1-HIF1A signaling axis that promotes glycolysis, which in turn functionally drives gastric cancer progression, and thereby provides a potential prognostic biomarker and therapeutic target.