Intrahepatic cholangiocarcinoma (ICCA), the second most prevalent primary liver malignancy, remains poorly understood at the molecular level. Research into the function of N6-methyladenosine (m6A) modification in the formation of ICCA and its potential as a therapeutic approach is being spurred by mounting evidence that it plays a crucial role in tumor biology. Immunohistochemical examination of patient samples in this investigation revealed a significant decrease in m6A methyltransferase METTL3 expression, accompanied by lower levels, which were associated with a lower overall survival rate. Functional assays demonstrated that the enforced expression of METTL3 inhibited ICCA cell proliferation and migration, while concurrently increasing the levels of the long non-coding RNA H19. Mechanistic experiments using RNA-binding protein immunoprecipitation and methylated RNA immunoprecipitation confirmed that METTL3 directly interacted with H19 and enhanced its m6A modification. Importantly, silencing of H19 reversed the growth- and migration-suppressive effects of METTL3, whereas H19 overexpression counteracted the phenotype induced by METTL3 downregulation. Further analysis revealed that the METTL3-H19 regulatory axis suppressed the expression of peroxisome proliferator-activated receptor gamma (PPARγ). Moreover, an oncolytic adenovirus engineered to overexpress H19, in combination with the PPARγ inhibitor BAY-4931, elicited potent antitumor effects both in vitro and in vivo. Collectively, these findings identify METTL3-mediated m6A modification of H19 as a critical suppressor of ICCA progression through modulation of PPARγ signaling. One interesting treatment option for ICCA may be the use of H19-armed oncolytic adenoviruses, especially when combined with PPARγ suppression.

BRCA1‑deficient triple‑negative breast cancer (TNBC) presents significant treatment challenges owing to the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) targets, exhibits marked molecular heterogeneity that precludes the application of effective targeted therapies, and harbors a highly immunosuppressive tumor microenvironment. Here, we used the Brca1co/co MMTV‑Cre mouse model that recapitulates human BRCA1‑mutant TNBC, characterized by early dominance of CD11b⁺Gr‑1⁻F4/80Low blood‑derived macrophages and subsequent enrichment of F4/80High tissue macrophages within adipose‑rich mammary glands. PD‑1 blockade with anti‑mPD‑1 monoclonal antibodies (mAb) significantly delayed primary tumor progression, reduced proliferation marker levels (PCNA, Ki‑67), enhanced apoptosis (as indicated by increased cleaved PARP levels), and selectively impaired PI3K/AKT signaling. In a post‑resection setting, anti-mPD-1 treatment extended recurrence‑free survival rates, with elevated CD4, CD8α, and cleaved PARP levels observed in recurrent tumors. Mice with the longest relapse‑free intervals exhibited the strongest T cell marker expression. A combination of focal 20 Gy irradiation and PD-1 blockade exerted a potent synergistic effect. Specifically, irradiation reduced extracellular matrix deposition and enhanced tumor cell apoptosis (evidenced by increased cleaved caspase-3 and cytosolic PCNA) while PD-1 blockade stimulated robust inflammatory responses, in particular, expansion of CD8α⁺ T cell infiltration. These mechanistic insights align with clinical strategies for TNBC that integrate DNA damaging agents and immunotherapy and validate this model as an optimal in vivo platform for preclinical evaluation of novel treatment modalities for BRCA1‑associated breast cancer.

Background: Hepatocellular carcinoma (HCC) exhibits limited therapeutic responses, partly due to undefined tumor suppressor networks. While TTC36 is downregulated in HCC and correlates with poor prognosis, its functional role, molecular mechanisms, and impact on targeted therapy remain unknown. Methods: By analyzing HCC tissues RNA-seq, and scRNA-seq data of HCC tissues, we investigated the expression pattern of TTC36. The clinical relevance was analyzed by using Kaplan-Meier Plotter. Cell proliferation, migration, invasion and apoptosis were detected to confirm the function of TTC36. Mechanistic insights into TTC36-mediated HCC suppression were obtained via RNA-seq analysis, mass spectrometry analysis, molecular docking, RNA pulldown, dual-luciferase reporter assays. In animal models, the tumor growth analysis, along with IHC staining and TUNNEL staining, was used to investigate the function of TTC36 and the response to sorafenib. Results: Bioinformatics and in vitro/vivo assays demonstrated TTC36 downregulation promotes HCC proliferation and correlates with poor survival. Mechanistically, TTC36 directly binds YBX3 and masks ubiquitination sites (K311/K350), inhibiting proteasomal degradation. Stabilized YBX3 enhances SPRED1 mRNA stability by binding the CACAUC motif in its 3'UTR, suppressing Ras/MAPK signaling. The TTC36/YBX3/SPRED1 axis inhibits tumor growth but induces sorafenib resistance via compensatory PI3K/Akt activation. Akt inhibition (MK-2206) reverses sorafenib resistance in TTC36-high HCC. Conclusion: TTC36 is a tumor suppressor that stabilizes YBX3 to upregulate SPRED1 and inhibit Ras/MAPK-driven proliferation. Paradoxically, TTC36-high HCC develops sorafenib resistance through PI3K/Akt hyperactivation, which is overcome by combined Akt inhibition. Thus, TTC36 may serves as a predictive biomarker to stratify HCC patients for personalized therapy: sorafenib monotherapy for TTC36-low tumors and sorafenib-Akt inhibitor combination for TTC36-high, sorafenib-resistant tumors.

Background: Tumor-associated macrophages (TAMs) are pivotal mediators of the immunosuppressive tumor immune microenvironment (TIME) in colorectal cancer (CRC). However, genes of TAMs that potentiate immunotherapy remain to be explored. Methods: Single-cell RNA sequencing (scRNA-seq) data were analyzed to identify TAM molecular signatures, which were validated in patient cohorts from Huadong Hospital and TCGA to explore their clinical significance. Multidimensional characterization of CRC TIME and Dipeptidyl peptidase VII (DPP7)-positive TAMs functional state was achieved through cytometry by time-of-flight, multiplex immunofluorescence, in vitro and in vivo experiments. Mechanistic investigations integrating RNA-seq, Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS)-based proteomics, and targeted lipid metabolomics have revealed the reprogramming of key metabolic pathways. Finally, the therapeutic potential of DPP7, which targets the enhancement of anti-PD-1 immunotherapy efficacy, was demonstrated. Results: DPP7 was identified as the key gene in TAMs, and DPP7+TAMs correlated with metastasis and worse overall survival in multiple clinical cohorts. Functional characterization demonstrated that DPP7+TAMs drove the immunosuppressive TIME and promoted the exhaustion of CD8+T cells, thus exhibiting M2-polarized features. Mechanistically, DPP7 reduced ubiquitination-induced degradation of Carnitine Palmitoyltransferase 1A (CPT1A) by binding to CPT1A in a mutually exclusive manner with TRIM25, thus enhancing fatty acid oxidation (FAO) in TAMs. This metabolic reprogramming consumes lipids (including triglycerides and free fatty acids), elevates adenosine triphosphate (ATP) generation, and induces an immunosuppressive phenotype. In vivo, DPP7 knockdown in bone marrow-derived macrophages (BMDMs) synergized with anti-PD-1 therapy, achieving significant suppression of subcutaneous xenograft tumor growth and liver metastatic burden by reversing the immunosuppressive TIME. Conclusions: DPP7 is mainly expressed in TAMs and DPP7+TAMs are strongly associated with adverse prognosis in CRC. Mechanistically, DPP7 enhances FAO to promote the M2-polarized phenotype in TAMs, leading to an immunosuppressive TIME. Targeting DPP7+TAMs may potentiate the efficacy of immunotherapy for CRC.

Papillary thyroid carcinoma (PTC) remains among the most prevalent endocrine malignancies globally, with its incidence steadily rising. Although clinical outcomes are generally favorable, a clinically significant subset of patients exhibits highly aggressive tumor phenotypes, characterized by larger tumor size and increased lymph node metastasis. Accumulating evidence implicates metabolic reprogramming and epigenetic dysregulation as pivotal drivers of tumor progression. Lactate, one of the byproducts of tumor metabolism, has recently garnered attention for its regulatory functions beyond metabolism. Histone lactylation, a recently identified epigenetic modification dynamically regulated by intracellular lactate accumulation, has emerged as an important regulator of tumor proliferation, metastasis, immune evasion, and therapeutic resistance. However, the functional implications and mechanistic underpinnings of histone lactylation in PTC remain largely unexplored. Here, we report significantly elevated pan-lysine lactylation and histone H3 lysine 18 lactylation (H3K18la) levels in clinical PTC specimens, with tumor tissues exhibiting markedly higher levels compared to adjacent normal thyroid tissues., correlating positively with aggressive clinicopathological features. Relevant cellular phenotypic assays further support this conclusion. Mechanistically, we demonstrate that H3K18la modification directly facilitates the transcriptional activation of Signal Transducer and Activator of Transcription 1 (STAT1). Activated STAT1 subsequently promotes transcriptional upregulation of Lactate Dehydrogenase A (LDHA), thereby enhancing lactate biosynthesis and establishing a self-perpetuating positive feedback loop. Consequently, tumor-derived lactate orchestrates and sustains malignant progression in PTC through this "H3K18la-STAT1-LDHA" regulatory axis. Collectively, our findings uncover a novel mechanistic linkage between tumor metabolism and epigenetic regulation in PTC, providing critical insights into thyroid cancer pathogenesis. Furthermore, therapeutic targeting of the H3K18la-STAT1-LDHA axis may represent an innovative and promising strategy to improve outcomes for patients with aggressive and refractory PTC.

Meningiomas (MGMs) are the most prevalent benign intracranial tumors in adults, with incidence markedly increasing with age, underscoring the need to explore aging-associated molecular mechanisms. In this study, we integrated transcriptomic datasets (GSE43290, GSE54934, GSE77259, and GSE183655) from the GEO database and aging-related genes (ARGs) from the Human Aging Genomic Resources to identify key genes implicated in MGM. We screened differentially expressed ARGs (ARG-DEGs) and conducted GO and KEGG pathway enrichment analyses, revealing significant involvement in cancer-related processes, viral infection pathways, and the FoxO signaling pathway. Using LASSO, SVM, CytoHubba-MCC, and MCODE algorithms, we identified two hub ARGs, SIRT1 and CEBPB. Immune infiltration analysis via ssGSEA indicated notable alterations in B cells, neutrophils, helper T cells, and regulatory T cells between MGM and healthy tissues, all closely associated with the hub genes. Furthermore, construction of a miRNA-TF-mRNA regulatory network highlighted the complex upstream regulation of these genes. Mendelian randomization analysis supported a potential causal relationship between SIRT1 and MGM development. Single-cell RNA sequencing data further confirmed heterogeneous expression of SIRT1 across key cell populations within MGM, brain-tumor interface, and dura mater tissues. These findings were validated through qRT-PCR and Western blot analyses, which demonstrated significant differences in SIRT1 expression at both the transcript and protein levels. Collectively, our study reveals that aging and immune dysregulation contribute to MGM pathogenesis and highlights SIRT1, in particular, as a potential diagnostic biomarker and therapeutic target, offering new insights into age-related mechanisms underlying MGM.

High expression of long noncoding RNA-encoding gene RP11-10C24.1 is associated with poor survival of patients with pancreatic cancer. This study aimed to investigate the role of RP11-10C24.1 in pancreatic cancer cell growth. The RNA sequencing and survival data of 177 patients with pancreatic cancer were acquired from TCGA to screen survival-associated lncRNAs. RNA BaseScope was used to retrospectively examine RP11-10C24.1 expression in 54 pairs of pancreatic cancer and paracancer samples of real-world patients. Fluorescence in situ hybridization (FISH) was conducted to localize RP11-10C24.1 transcripts in pancreatic cancer cells. Knockdown of RP11-10C24.1 was performed to investigate the role of RP11-10C24.1 in the behavior of pancreatic cancer cells in vitro and in vivo. Western blot analysis was carried out to identify the functional targets downstream of RP11-10C24.1. High expression of RP11-10C24.1 was associated with poor survival of the TCGA cohort. RP11-10C24.1 expression was significantly increased in pancreatic cancer tissue compared with that in paracancer tissue. FISH analysis demonstrated that RP11-10C24.1 transcript was localized in the cytoplasm of pancreatic cancer cells. In PANC-1, SW1990, and AsPC-1 cells, knockdown of RP11-10C24.1 inhibited cell proliferation, migration, and invasion while promoting cell apoptosis. Knockdown of RP11-10C24.1 suppressed the growth of AsPC-1 tumor xenografts in mice. Furthermore, knockdown of RP11-10C24.1 attenuated protein expression of multiple cancer-associated genes, including fibronectin 1 (FN1), in PANC-1 cells. Importantly, overexpression of FN1 effectively reversed the suppressive effect of RP11-10C24.1 silencing on pancreatic cell proliferation and invasion. In conclusion, knockdown of RP11-10C24.1 inhibits pancreatic cancer cell growth through downregulating FN1 expression.

Nasopharyngeal carcinoma (NPC) is a malignant tumor with high metastatic potential and poor prognosis due to late diagnosis and frequent metastasis. Circular RNAs (circRNAs) have emerged as essential regulators in tumor growth, yet the functional role of circCGNL1 in NPC remains unexplored. Expression of circCGNL1 and IGF2BP3 was examined in NPC tissues and cell lines using qRT-PCR and western blot. The circular nature, subcellular localization, and stability of circCGNL1 were validated through RNase R digestion, actinomycin D treatment, and FISH assay. Functional roles of circCGNL1 and IGF2BP3 were assessed by CCK-8, EdU, TUNEL, flow cytometry, Transwell, colony formation, and wound-healing assays. Protein-RNA interactions were evaluated using RIP, RNA pull-down, and immunofluorescence co-localization. In vivo tumorigenicity was analyzed using a subcutaneous xenograft model in BALB/c nude mice. circCGNL1 was notably downregulated in NPC tissues and cell lines and exhibited cytoplasmic localization and high stability. In vitro, overexpression of circCGNL1 inhibited NPC cell proliferation, migration, and invasion while increasing apoptosis, and in vivo, it reduced tumor development. IGF2BP3, an oncogenic RNA-binding protein, was upregulated in NPC and promoted tumor progression. Mechanistically, circCGNL1 directly interacted with IGF2BP3 and negatively regulated the AKT/mTOR pathway by reducing phosphorylation of AKT and mTOR. Rescue assays further revealed that circCGNL1 inhibited NPC cell proliferation, migration, and invasion while increasing apoptosis by suppressing the activation of the AKT/mTOR signaling. This study identifies circCGNL1 as a tumor-suppressive circRNA that inhibits NPC progression by binding to IGF2BP3 and suppressing the AKT/mTOR signaling. These findings reveal a novel regulatory mechanism in NPC and highlight circCGNL1 as a promising biomarker and therapeutic target.

Real-world data on afatinib for patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) G719X + S768I co-mutations remains limited. This study aims to evaluate the efficacy and safety of afatinib in a relatively large cohort of NSCLC patients with these uncommon mutations in Xuanwei and Fuyuan counties, China.

Docetaxel (DTX) is widely used in lung cancer (LC), but its therapeutic efficacy is limited due to frequent development of chemoresistance. Epigenetic regulation via N6-methyladenosine (m6A) has been implicated in tumor progression and drug resistance. The mechanisms underlying the biological resistance of methyltransferase-like 14 (METTL14) and dickkopf 4 (DKK4) in LC remain incompletely understood. The expression levels of mRNA and protein of DKK4 and METTL14 were detected through RT-qPCR and western blot analysis. DTX was administered to A549 and H1299 cells for the establishment of DTX-resistant cell lines (A549/DTX and H1299/DTX). Half maximal inhibitory concentration (IC50) of A549/DTX and H1299/DTX cells was tested by Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. The detection of cell proliferation was carried out by EdU. Flow cytometry was utilized to analyze cell cycle, apoptosis, and M2 macrophage proportion. Transwell was employed to assess cell migration and invasion. The m6A level was measured using methylated RNA Immunoprecipitation (MeRIP) assay. A mouse xenograft model was established for the purpose of analysis in vivo. DKK4 and METTL14 were upregulated in LC and significantly increased in A549/DTX and H1299/DTX cells. The downregulation of DKK4 led to diminished proliferation, cell cycle arrest, increased apoptosis, decreased cell migration and invasion, and reduced proportion of M2 macrophages in A549/DTX and H1299/DTX cells. DKK4 enhanced DTX resistance in LC in vivo. METTL14 stimulated the m6A methylation of DKK4 mRNA. METTL14 facilitated the malignant growth of DTX-resistant cells and the polarization of M2 macrophages by modulating DKK4 expression. METTL14 targeting DKK4 influenced LC progression and DTX resistance, indicating that METTL14 could serve as a potential therapeutic target to overcome DTX resistance in clinical settings.

Melanoma differentiation-associated gene-7 (Mda-7) selectively suppresses growth and induces apoptosis in various tumor cells without harming normal cells. Inhibition of autophagy has been shown to enhance the efficacy of many cancer therapies. However, its effect on the anticancer activity of adenoviruses expressing melanoma differentiation-associated gene-7 (Ad/Mda-7) in glioblastoma (GBM) has remained unclear. This study investigated the combined effect of an autophagy inhibitor (chloroquine [CQ]) and Mda-7 in U87 cancer cells.

RNA methylation has emerged as a pivotal layer of post-transcriptional regulation that shapes the biological behavior of cancer cells. Among the diverse chemical modifications identified-such as N6-methyladenosine (m6A), N1-methyladenosine (m1A), 5-methylcytosine (m5C), 7-methylguanosine (m7G), 5-hydroxymethylcytosine (5hmC), and 2'-O-dimethyladenosine (m6Am)-the m7G modification has recently garnered increasing attention. Mounting evidence indicates that m7G methylation plays an essential role in RNA metabolism and profoundly influences cancer initiation and progression.

Accurate molecular subtyping is essential for guiding precision treatment and prognostic stratification in endometrial cancer (EC). However, current methods, based on Sanger sequencing and immunohistochemistry (IHC), are costly, time-intensive, and difficult to implement widely in routine clinical practice, particularly in resource-limited settings. To overcome these challenges, we developed a deep-learning pipeline that directly infers EC molecular subtypes from routine hematoxylin-and-eosin (H&E) whole-slide images (WSIs). The framework integrates super-resolution enhancement (SRResGAN), transformer-based lesion segmentation (MedSAM), and a ResNet-101 classifier for molecular subtype prediction, with an LSTM module for survival modeling. This retrospective study included 393 Chinese patients diagnosed between 2010 and 2018, all with ≥ 5 years of follow-up. Molecular subtypes-POLEmut, mismatch repair-deficient (MMRd), p53abnormal (p53abn), and no specific molecular profile (NSMP)-were confirmed by Sanger sequencing and immunohistochemistry. The model achieved high classification accuracies (92% for POLEmut and MMRd, 91% for p53abn, and 90% for NSMP), with a strong correlation between predicted and observed survival (R2 = 0.9692; MAE = 123 days). External validation on two independent cohorts (N = 35 and N = 83) confirmed robust generalizability across institutions. This study represents the first large-scale, multicenter, AI-based digital pathology model for EC molecular classification in China. The proposed workflow provides an automated, interpretable, and cost-efficient alternative to conventional molecular testing, supporting precision oncology, fertility-preserving management, and clinical decision-making in real-world practice.

As a predominant form of cancer affecting male populations, prostate cancer (PCa) demonstrates notably high incidence rates globally. The significant heterogeneity in tumor microenvironment (TME) composition (including epithelial and diverse cell populations) hinders clear interpretation of gene and biomarker roles in disease advancement and immune response modulation. Through combined analysis of bulk and single-cell RNA sequencing data, this investigation evaluates prostate cancer-related genes' clinical relevance and prognostic potential.

Esophageal squamous cell carcinoma (ESCC) is a lethal malignancy with limited therapeutic options, primarily due to its aggressive metastatic behavior. This study aimed to elucidate the molecular drivers of ESCC metastasis by identifying a critical oncogene and investigate its functional mechanisms.

Cell-free DNA (cfDNA) fragmentation patterns reflect epigenetic modifications and are promising biomarkers for early cancer detection. While integrating diverse fragmentomic signals can improve accuracy, high modality dimensionality, and limited samples challenge effective multimodal fusion. We present Early-Late fusion with Sample-Modality evaluation (ELSM), a two-stage neural network integrating 13 fragmentomic feature spaces with sample-wise modality evaluation to capture complementary signals. Across five datasets of 1994 samples from 10 cancer types, ELSM outperforms unimodal and advanced multimodal models for cancer detection and tissue-of-origin prediction, achieving an AUC of 0.972 for pan-cancer diagnosis and 0.922 in an independent gastric cancer cohort, with a median tissue-of-origin accuracy of 0.683. Analysis of key genomic regions identified by ELSM reveals robust interpretability aligned with known oncogenic pathways. ELSM provides a powerful and interpretable framework for integrative multi-omics analysis with strong potential for clinical translation in early cancer detection.

Skin cutaneous melanoma (SKCM) is a highly aggressive skin cancer with poor prognosis in advanced stages, despite recent advances in immunotherapy and targeted treatments. Novel therapeutic targets are urgently needed to improve the patient outcomes. Scavenger receptor class A member 5 (SCARA5), a scavenger receptor widely expressed in various human tissues, has been reported to act as a tumor suppressor in multiple cancers. The expression level of SCARA5 in SKCM tissues and cell lines was analyzed using the Gene Expression Profiling Interactive Analysis (GEPIA) database and validated by Western blotting. SKCM cells were transfected with SCARA5 overexpression plasmids, and cell proliferation, migration, and apoptosis were assessed using Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, and Transwell assays. Ferroptosis-related changes were examined by detecting intracellular Fe2, lipid Reactive Oxygen Species (ROS), and malondialdehyde (MDA) levels. Additionally, the expression of ferroptosis-associated proteins glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4), and SLC7A11 was analyzed by Western blotting. SCARA5 expression was markedly downregulated in SKCM cells compared with normal skin cells. Restoration of SCARA5 expression significantly suppressed the proliferation and migration of SKCM cells. Further analysis revealed that SCARA5 overexpression induced ferroptosis, as evidenced by increased levels of Fe2, lipid ROS, and MDA. Mechanistically, SCARA5 regulated the ferroptosis process through modulation of the GPX4/ACSL4 pathway. CARA5 inhibits SKCM progression by promoting ferroptosis and disrupting the GPX4/ACSL4 axis.

Identifying fatty acid metabolism (FAM)-related molecular signatures to construct a prognostic model for multiple myeloma (MM) patients.

Glycolysis, a central process of cellular energy metabolism, has been shown to be closely associated with the development of hepatocellular carcinoma (HCC). This study aimed to investigate the prognostic value of the glycolysis gene set (GGS) in HCC.

The stemness of tumor cells is closely associated with immune infiltration and may influence both the prognosis of osteosarcoma and alterations in the tumor microenvironment.