To identify shared molecular mechanisms and crosstalk genes (CGs) between diffuse large B-cell lymphoma (DLBCL) and primary Sjögren's syndrome (PSS), and to explore the role of MICA in the immune microenvironment (IME).

Interferon-gamma (IFNγ) is a pivotal cytokine in immune surveillance and inflammation, yet its precise role in colorectal cancer (CRC) remains controversial due to its dual involvement in tumor suppression and immune evasion. Although natural killer cell receptor (NKR)+CD8+ T cells and invariant natural killer T (iNKT) cells contribute to anti-tumor immunity, how these cells regulate CRC progression under IFNγ-mediated, inflammatory conditions remains unclear.

Burkitt lymphoma (BL) is a highly aggressive malignancy with limited effective treatments due to toxicity/resistance. Identifying and prioritizing candidate biomarkers and potential therapeutic targets from complex transcriptomic data, ahead of functional validation, remains a major unmet need.

The chemokine‑like factor (CKLF)‑like MARVEL transmembrane domain‑containing (CMTM) family belongs to the human CKLF gene superfamily, which comprises CKLF and CMTM1‑8. Among its members, CMTM6 encodes a protein exhibiting structural and functional characteristics that lie between classical chemokines and tetraspanins. CMTM6 is expressed in several normal tissues, including those of the immune, reproductive and nervous systems. Notably, its expression is frequently upregulated across a broad spectrum of tumors including, but not limited to, carcinomas of the lung, liver and gastrointestinal tract. CMTM6 contributes to tumor proliferation, invasion and metastasis by inhibiting immune responses, facilitating immune evasion and inducing epithelial‑mesenchymal transition, thereby influencing patient prognosis and survival outcomes. The present review systematically summarizes the molecular functions, mechanisms of action, disease‑related expression patterns and clinical translational applications of CMTM6, aiming to provide novel clinical insights and to guide the development of CMTM6‑targeted therapeutic strategies.

The tumor immune microenvironment plays a decisive role in tumor initiation, progression and therapeutic response. Spatial transcriptomics (ST) enables comprehensive analysis of the whole transcriptome or specific gene sets while preserving the original spatial location information within tissues, offering a revolutionary approach to unraveling the complexity of the tumor immune microenvironment in the spatial dimension. The present review aims to systematically elaborate on the role and application of ST in deciphering the tumor immune microenvironment. Focusing on tumor microenvironment niches at different stages of tumor progression, from precancerous lesions and locally advanced tumors to distant metastasis, recent advances in ST for mapping the spatial distribution and functional states of key cell subpopulations are summarized. The present review further highlights its potential for clinical translation in identifying spatially defined biomarkers and elucidating the mechanisms underlying therapeutic responses and analyze the key technical challenges that constrain the application of ST in clinical practice. In recent years, the rapid development of machine learning algorithms has provided new opportunities to overcome the technical limitations of ST. The deep integration of machine learning with ST is laying a solid theoretical foundation and technical support for precision medicine and early intervention.

MicroRNAs (miRNAs or miRs) represent conserved non‑coding RNAs responsible for the regulation of gene expression in a post‑transcriptional manner. The dysregulation of miRNAs often leads to disease development and progress. In particular, miR‑200c is one of the miR‑200 family members, which is found deregulated in various pathologies and involved in the process of cancer progression through its participation in different molecular signaling pathways. Initially, miR‑200c was regarded as an essential factor in metastases formation. Nevertheless, following the increase in knowledge about cell death signaling pathways, it became clear that miR‑200c participates in various types of cell death such as apoptosis, autophagy and pyroptosis. The present narrative review primarily discusses the molecular mechanisms through which miR‑200c regulates apoptosis, pyroptosis and autophagy and explores its potential therapeutic value.

Glycosylation is a common post-translational modification in mammalian cells. Abnormal glycosylation is a universal feature of cancer cells, regarded as a hallmark of cancer, and can influence tumor progression, including cell adhesion, migration, growth, differentiation, and invasion. A key change in N-glycosylation involves the modification of bisecting N-acetylglucosamine (GlcNAc), which is catalyzed by N-acetylglucosaminyltransferase III (GnT-III, encoded by the MGAT3 gene). GnT-III is widely regarded as a key glycosyltransferase in N-glycan biosynthesis. The addition of a bisecting GlcNAc prevents further processing of N-glycans, thereby blocking the synthesis of GlcNAc-branched N-glycans by N-acetylglucosaminyltransferase IV (GnT-IV) and N-acetylglucosaminyltransferase V (GnT-V). These branched N-glycans are strongly associated with cancer invasion and metastasis. For example, in many cases, integrins and E-cadherin are modified by GnT-V, which promotes cell migration and cancer invasion. In contrast, those modified by GnT-III tend to inhibit cell migration and metastasis. Recent studies also show that GnT-III expression suppresses cancer chemoresistance caused by prolonged exposure to anticancer drugs and enhances the differentiation capacity of leukemia cells. This review will discuss the roles of GnT-III in cancer cell behavior and cellular signaling, with a particular focus on some potential target proteins.

APOBEC cytidine deaminases generate characteristic TCW-context mutations that diversify cancer genomes, yet their functional impact on colorectal cancer (CRC) progression and the tumor microenvironment (TME) remains poorly defined.

Although cullin-family E3 ubiquitin ligases regulate diverse oncogenic pathways, the role of CACUL1 in hepatocellular carcinoma (HCC) remains poorly characterized.

Stomach adenocarcinoma (STAD) is characterized by significant heterogeneity, within which myeloid cells play crucial yet incompletely understood roles. The relationship between the functional states of myeloid cells, patient prognosis, and therapeutic response requires further elucidation.

Homozygous deletion of the methylthioadenosine phosphorylase (MTAP) gene is a frequent genetic alteration in cancer. The MTAP enzyme, which creates adenine from 5'-methylthioadenosine (MTA), is constitutively expressed in all tissues throughout the body. Previously, we described a novel strategy to specifically target MTAP-deleted cancer cells by combining the antipurine prodrug 2-fluoroadenine (2FA) with MTA. In vitro, this combination efficiently kills MTAP- cancer cells while leaving MTAP+ cells unharmed. However, in vivo, the combination was less effective at tumor cell killing, resulting in slower growth but not tumor regression. In this study, we show that this effectiveness difference is associated with a large difference in the amount of 2FA that is incorporated into 2FA-containing nucleotides. To explain this observation, we tested the hypothesis that 2FA was a target for the purine metabolic enzyme xanthine oxidase (XO), which is found in various extracellular fluids. In vitro, the addition of XO protein to culture media effectively abolishes killing by 2FA, and this effect can be fully reversed by the addition of febuxostat (FX), a XO inhibitor. In vivo, the addition of FX to 2FA results in increased cell killing and toxicity, and a 1,000% increase in the amount of 2FA that is converted to its active form, 2FA-monophosphate. Xenograft studies using MTAP- HT1080 and MiaPaCa-2 cell lines show that a 2FA/MTA/FX cocktail can cause tumor regression in vivo. These studies suggest that a combination of 2FA/MTA/FX may be useful in treating MTAP- cancer.

We undertook this study to investigate the effect of exosomal microRNA-143-3p (miR-143-3p) on the biological behavior and angiogenesis in breast cancer. We transfected human breast cancer cells (MDA-MB-231) with miR-143-3p Agomir or Agomir-NC, and we isolated the exosomes (ex) that were secreted and named these miR-143-3p Agomir-ex and Agomir-NC-ex, respectively. We performed real-time polymerase chain reaction (real-time PCR) to detect the level of exosomal miR-143-3p. We treated the MDA-MB-231 cells with exosomal miR-143-3p Agomir-ex and Agomir-NC-ex. We measured the cellular miR-143-3p concentration using real-time PCR, cell proliferation using the cell counting kit-8 (CCK-8), apoptosis using flow cytometry, the abilities of cell migration and invasion using FCM (flow cytometry), and the levels of vascular endothelial growth factor (VEGF) in cell supernatants using the enzyme-linked immunosorbent assay (ELISA). We constructed nude mouse MDA-MB-231 cell transplantation tumor models and injected Agomir-NC, miR-143-3p Agomir, Agomir-NC-ex, and miR-143-3p Agomir-ex intratumorally to observe the tumor growth. Next, we isolated the tumor tissues and measured the expression of miR-143-3p, pathological change, apoptosis, levels of Ki67, VEGF, and CD31, and microvessel density using real-time PCR, hematoxylin and eosin (HE) staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and immunohistochemistry, respectively. We found that, in comparison with Agomir-NC-ex, the expression of miR-143-3p was upregulated in miR-143-3p Agomir-ex, and miR-143-3p Agomir-ex increased the levels of miR-143-3p in breast cancer cells, inhibited the proliferation, migration, and invasion of breast cancer cells, promoted apoptosis, and decreased the levels of VEGF in the cell supernatant. Our experiments with the nude mouse transplantation tumor revealed that both miR-143-3p Agomir-ex and miR-143-3p Agomir reduced tumor growth and the expression of Ki67 protein, increased the levels of miR-143-3p, promoted tumor cell apoptosis, and inhibited the expressions of CD31 protein and VEGF, and angiogenesis. In our current study, we found that the exosomal miR-143-3p inhibited malignant biological behavior and angiogenesis in breast cancer.

The human genome encodes ~1,900 secreted proteins, many of which mediate intercellular communication. Secreted proteins do not act cell-autonomously, limiting systematic approaches to characterize their functions. Here we introduce SecAct (Secreted Activity, https://secact.ccr.cancer.gov ), a computational framework that infers the signaling activities of 1,170 human secreted proteins from spatial, single-cell and bulk transcriptomic data. The inference model harnesses precomputed intercellular signaling signatures trained on 1,258 spatial transcriptomics samples spanning 37 cancer types. Transcriptomics data from antisecreted protein therapies validate SecAct's accuracy in predicting the repression of secreted protein activity following treatment. For spatial and single-cell transcriptomics data, SecAct provides interactive modules for analyzing secreted protein-mediated cell-cell communication. Applying SecAct to 54 cancer immunotherapy cohorts comprising 5,174 patients, we identified secreted proteins associated with tumor immunity. In vivo experiments validated lymphocyte antigen 86 (LY86), whose function in cancer was previously unknown, as an antitumor regulator.

The acidic tumor microenvironment (TME) is a major driver of immunosuppression and tumor progression in breast cancer. Although myosin VI (MYO6), an actin-dependent motor protein, is frequently upregulated in malignancies, its function in immune remodeling remains poorly understood.

Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder characterized by significant reproductive and metabolic complications. Insulin resistance (IR) plays a central role in the pathophysiology of PCOS and contributes to several associated metabolic abnormalities. This review highlights the key mechanisms underlying PCOS, including IR, hyperandrogenism, cardiovascular disease, gut microbiota dysbiosis, and the increased risk of type 2 diabetes mellitus (T2DM), along with current and emerging therapeutic strategies for improving disease outcomes. Accumulating evidence suggests that genetic predisposition contributes to PCOS susceptibility. Polymorphisms in genes such as the androgen receptor (AR), cytochrome P450 17A1 (CYP17), and follicle-stimulating hormone receptor (FSHR) have been associated with altered steroidogenesis and ovarian dysfunction, thereby influencing disease severity. In addition to genetic factors, environmental influences, including exposure to endocrine-disrupting chemicals (EDCs) and air pollution, may exacerbate metabolic disturbances and increase the risk of developing PCOS. Conventional therapeutic approaches focus on improving insulin sensitivity and correcting hormonal imbalances. These include pharmacological treatments such as metformin, oral contraceptives, and lifestyle modifications involving diet and physical activity. Recently, novel therapeutic strategies have emerged, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), microRNA-based therapies, and interleukin-22 (IL-22)-mediated interventions, which show potential in targeting IR and metabolic dysfunction in PCOS. Furthermore, modulation of gut microbiota through probiotics, prebiotics, and fecal microbiota transplantation (FMT) represents an emerging strategy for restoring metabolic homeostasis. Overall, a comprehensive and personalized therapeutic approach integrating pharmacological, lifestyle, and microbiome-targeted interventions may significantly improve PCOS management and reduce long-term metabolic and reproductive complications.

IntroductionDysregulated epidermal growth factor receptor (EGFR) signaling is a key mechanism driving cancer progression and metastasis. Owing to its frequent overexpression in pancreatic cancer (PCa), EGFR has become a desirable molecular target for targeted therapies. XYZ-I-73 (N-(5-fluoro-2-oxo-1-(tetrahydrofuran-2-yl)-1,2-dihydropyrimidin-4-yl) dodecanamide), a structural analog of 5-fluorouracil (5-FU), has been previously synthesized and shown to exhibit cytotoxicity against PCa cells.MethodsXYZ-I-73 was entrapped in liposomes via thin-film hydration and subsequently conjugated to EGFR antibodies to produce an immunoliposome formulation- Ab-XYZ-I-73LnP (where 'Ab' denotes antibody-conjugated and 'LnP' denotes liposomal nanoparticle). In vitro efficacy was assessed by measuring cell viability and apoptosis in MiaPaCa-2 and PANC-1 cells, while pharmacokinetics and antitumor efficacy were determined in a cell line-derived xenograft (CDX) mouse model.ResultsAb-XYZ-I-73LnP exhibited a mean particle size of 143nm ± 2.3, PDI (0.37), and zeta potential -46.2 ± 1.3mV. In MiaPaCa-2 cells, Ab-XYZ-I-73LnP showed remarkably higher cytotoxicity than 5-FU in both 2D (IC50 = 2.5 ± 0.9μM vs 13.2 ± 1.1μM) and 3D cultures (IC50 = 8.1 ± 1.1μM vs 26.7 ± 1.1 μM). Similarly, in PANC-1 cells, Ab-XYZ-I-73LnP showed lower IC50 values compared to 5-FU;2D (IC50 = 2.9 ±1.1 μM vs 20.4±1.2 μM), 3D (IC50 = 12.9 ± 0.6μΜ vs 37.1±0.9 μM). Pharmacokinetic analysis revealed a prolonged half-life for Ab-XYZ-I-73LnP compared with free 5-FU (t1/2 = 1.62 ± 0.03 h vs 0.49 ± 0.01 h, p < 0.001). There was about a 2-fold increase in the area under the curve (AUC) for Ab-XYZ-I-73LnP compared to 5-FU (AUC= 0.32 ± 0.04µg/(L*hr) vs 0.15 ± 0.02µg/(L*hr), p<0.01).ConclusionOverall, the study supports the formulation of an immunoliposome of modified 5-FU, which may significantly enhance drug bioavailability and therapeutic potential for the treatment of PCa.

The mechanisms underlying the interactions between disseminated tumor cells (DTCs) and their tissue microenvironment during metastatic colonization are currently poorly understood. We integrated multimodal single-cell and spatial profiling from liver cancer mouse models and human metastases to track the spatiotemporal dynamics of DTCs and their microenvironments from single-cell seeding to overt lung metastasis. We identified a residual population of quiescent Phgdhhigh DTCs that survived initial innate immune clearance and became transiently enriched in micrometastases. These cells shaped an immune-scarce microenvironment through PHGDH-dependent, H3K27me3-mediated epigenetic silencing of chemokine transcription, thereby promoting metastatic expansion. Cx3cr1high interstitial macrophages were also transiently enriched before DTC expansion, creating an immune-privileged niche for metastatic outgrowth by recruiting immunosuppressive cells. Inactivating the PHGDH-H3K27me3 axis in DTCs or depleting interstitial macrophages restored immune surveillance and inhibited metastatic colonization. These findings provide insights into the development of micrometastasis-targeting regimens.

More than 600,000 cases of head and neck squamous cell carcinoma (HNSCC) are diagnosed globally each year. Many HNSCCs overexpress the ERBB family member epidermal growth factor receptor (EGFR), and EGFR inhibitors (EGFRi) and pan-ERBB inhibitors (ERBBi) are clinically active in the treatment of locally advanced, metastatic, or recurrent HNSCC. However, resistance to these inhibitors typically develops, often associated with epithelial-mesenchymal transition (EMT). Aurora kinase A (AURKA), a mitotic regulator with expanded signaling functions in tumors, has been reported to reverse EGFR resistance in EGFR-mutated lung cancer. To identify strategies to overcome resistance in HNSCC, we developed HNSCC cell models that were treatment-naïve parental or selected for resistance to the EGFRi erlotinib or the ERBBi afatinib. The resistant HNSCC models had typically undergone partial EMT, consistent with clinical resistance, associated with upregulation of the AURKA partner protein NEDD9. Synergy of the AURKA inhibitor VIC-1911 with erlotinib or afatinib in parental models was reduced in resistant models in short-term growth assays. In longer-term clonogenic assays and in vivo, cells selected for EGFRi/ERBBi resistance showed heightened sensitivity to VIC-1911, contributing to reduced synergy. Based on increased AURKA dependence, we compared the combination of VIC-1911 with adavosertib, an inhibitor of the cell-cycle checkpoint regulator WEE1, in parental and resistant models. These showed a combination effect both in vitro and in vivo that was retained in ERBBi-resistant xenografts, suggesting the potential value of combined AURKA and WEE1 inhibitor use in patients with ERBBi-resistant HNSCC.

The treatment of non-small cell lung cancer (NSCLC) has challenges such as drug resistance and recurrence. Concurrently, the induction of apoptosis and ferroptosis is a promising therapeutic strategy. This study aimed to investigate whether the natural product, verbascoside, induces apoptosis and ferroptosis in NSCLC cells by targeting BCAT2.

Papillary thyroid microcarcinomas (PTMCs) account for about 30% of papillary thyroid cancer cases, and the BRAF V600E mutation is one of the driver mutations in the development of papillary thyroid carcinomas. However, traditional molecular diagnostic methods are time-consuming and costly, highlighting the need for alternative approaches, such as machine learning-based analysis of histopathological images.