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Exosomes are closed-membrane nanovesicles that are secreted by a variety of cells and exist in most body fluids. Recent studies have demonstrated the potential of exosomes as natural vehicles that target delivery of functional small RNA and chemotherapeutics to diseased cells. In this study, we introduce a new approach for the targeted delivery of exosomes loaded with functional miR-26a to scavenger receptor class B type 1-expressing liver cancer cells. The tumor cell-targeting function of these engineered exosomes was introduced by expressing in 293T cell hosts, the gene fusion between the transmembrane protein of CD63 and a sequence from Apo-A1. The exosomes harvested from these 293T cells were loaded with miR-26a via electroporation. The engineered exosomes were shown to bind selectively to HepG2 cells via the scavenger receptor class B type 1-Apo-A1 complex and then internalized by receptor-mediated endocytosis. The release of miR-26a in exosome-treated HepG2 cells upregulated miR-26a expression and decreased the rates of cell migration and proliferation. We also presented evidence that suggest cell growth was inhibited by miR-26a-mediated decreases in the amounts of key proteins that regulate the cell cycle. Our gene delivery strategy can be adapted to treat a broad spectrum of cancers by expressing proteins on the surface of miRNA-loaded exosomes that recognize specific biomarkers on the tumor cell.

Smoking is one of the most impactful lifestyle-related risk factors in many cancer types including esophageal squamous cell carcinoma (ESCC). As the major component of tobacco and e-cigarettes, nicotine is not only responsible for addiction to smoking but also a carcinogen. Here we report that nicotine enhances ESCC cancer malignancy and tumor-initiating capacity by interacting with cholinergic receptor nicotinic alpha 7 subunit (CHRNA7) and subsequently activating the JAK2/STAT3 signaling pathway. We found that aberrant CHRNA7 expression can serve as an independent prognostic factor for ESCC patients. In multiple ESCC mouse models, dextromethorphan and metformin synergistically repressed nicotine-enhanced cancer-initiating cells (CIC) properties and inhibited ESCC progression. Mechanistically, dextromethorphan non-competitively inhibited nicotine binding to CHRNA7 while metformin downregulated CHRNA7 expression by antagonizing nicotine-induced promoter DNA hypomethylation of CHRNA7 . Since dextromethorphan and metformin are two safe FDA-approved drugs with minimal undesirable side-effects, the combination of these drugs has a high potential as either a preventive and/or a therapeutic strategy against nicotine-promoted ESCC and perhaps other nicotine-sensitive cancer types as well.

Biofilms protect bacteria from antibiotics and this can produce drug-resistant strains, especially the main pathogen of periodontitis, . Carbon quantum dots with various biomedical properties are considered to have great application potential in antibacterial and anti-biofilm treatment. Tinidazole carbon quantum dots (TCDs) and metronidazole carbon quantum dots (MCDs) were prepared by a hydrothermal method with the clinical antibacterial drugs tinidazole and metronidazole, respectively. Then, TCDs and MCDs were characterized by transmission electron microscopy, UV-visible spectroscopy, infrared spectroscopy and energy-dispersive spectrometry. The antibacterial effects were also investigated under different conditions. The TCDs and MCDs had uniform sizes. The results of UV-visible and energy-dispersive spectrometry confirmed their important carbon polymerization structures and the activity of the nitro group, which had an evident inhibitory effect on , but almost no effect on other bacteria, including , and . Importantly, the TCDs could penetrate the biofilms to further effectively inhibit the growth of under the biofilms. Furthermore, it was found that the antibacterial effect of TCDs lies in its ability to impair toxicity by inhibiting the major virulence factors and related genes involved in the biofilm formation of , thus affecting the self-assembly of biofilm-related proteins. The findings demonstrate a promising new method for improving the efficiency of periodontitis treatment by penetrating the biofilm with preparations of nano-level antibacterial drugs.

In China, esophageal cancer (EC) is one of the most prevalent malignant tumors of the digestive system. EC has a high incidence and mortality rate, of which esophageal squamous cell carcinoma (ESCC) accounts for more than 90%. Due to a lack of effective prevention and treatment methods, the 5 year survival rate is less than 30%. In recent years, microecology has become a hot spot in cancer research, and dysbiosis may play an important role in the etiology of EC. Presently, research on the relationship between the microbiome and ESCC remains in its early stages. This narrative review examines the relationship between the oral and esophageal microbiota and ESCC. A better understanding of this relationship may facilitate early detection and the optimization of treatment strategies.

Esophageal squamous cell carcinoma (ESCC) represents a major therapeutic challenge due to the rapid development of resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Recent evidence highlights that this resistance is driven not only by genetic mutations but also by spatial heterogeneity of tumor microenvironments and compensatory signaling mechanisms. In this review, we propose a “spatial-signaling-intervention” framework with a particular focus on the NTRK2/MAPK signaling axis, which plays dual roles in signaling compensation and immune evasion. By integrating spatial multi-omics, proteomics, and AI-assisted topological modeling, three resistant niches are identified: (1) cancer stemness-enriched zones, (2) MAPK hyperactive islands, and (3) immune-cold regions. Based on this atlas, we design precision nanotherapeutic platforms, including responsive, dual-target, and feedback-loop nanocarriers, to selectively modulate resistant spatial niches. Preclinical validation in patient-derived xenografts and organoid models further demonstrates the translational potential of these strategies. This work provides a conceptual and technological roadmap for overcoming EGFR-TKI resistance in ESCC. Atlas-guided nanocarrier systems offer a promising avenue for spatially targeted and feedback-responsive therapy, highlighting the role of pharmaceutics in advancing precision oncology.

There is an unmet need for additional and more efficacious therapies for patients with unresectable metastatic oesophageal cancer. We aimed to evaluate the efficacy and safety of adding tiragolumab and atezolizumab to chemotherapy as first-line treatment for unresectable or metastatic oesophageal squamous cell carcinoma. The SKYSCRAPER-08 randomised, double-blind, placebo-controlled, phase 3 trial was done at 67 centres in mainland China, South Korea, Thailand, Taiwan, and Hong Kong and enrolled adult patients (aged ≥18 years) with treatment-naive, unresectable locally advanced, unresectable recurrent, or metastatic oesophageal squamous cell carcinoma, with an Eastern Cooperative Oncology Group performance status of 0–1. Patients were randomly assigned (1:1) to receive tiragolumab (600 mg) plus atezolizumab (1200 mg) and chemotherapy (paclitaxel [175 mg/m2] and cisplatin [60–80 mg/m2]) or placebo and chemotherapy through intravenous infusion for six 21-day cycles. The primary outcomes were independent review facility-assessed progression-free survival and overall survival in the intention-to-treat population (defined as all randomly assigned patients, regardless of whether they received any study treatment). This study was registered with ClinicalTrials.gov, NCT04540211, and is ongoing. Between Oct 30, 2020, and Nov 30, 2021, 461 patients were assigned to receive tiragolumab plus atezolizumab and chemotherapy (n=229) or placebo and chemotherapy (n=232); 406 (88%) were male and 55 (12%) female, and all patients were Asian. Median survival follow-up was 12·6 months (IQR 6·8–18·0). Median independent review facility-assessed progression-free survival (cutoff June 15, 2022) in the tiragolumab plus atezolizumab and chemotherapy group was 6·2 months (95% CI 5·7–7·2) versus 5·4 months (95% CI 4·4–5·5) in the placebo and chemotherapy group (HR 0·56, 95% CI 0·45–0·70; p<0·0001). Median overall survival (cutoff Feb 13, 2023) was 15·7 months (95% CI 13·3–20·4) and 11·1 months (95% CI 9·6–13·6; HR 0·70, 95% CI 0·55–0·88; p=0·0024). The most common grade 3–4 adverse events in the tiragolumab plus atezolizumab and chemotherapy group versus the placebo and chemotherapy group were white blood cell count decrease (46 [20%] of 228 vs 35 [15%] of 227), neutrophil count decrease (78 [34%] vs 78 [34%]), and anaemia (19 [8%] vs 24 [11%]). Serious adverse events occurred in 94 (41%) of 228 patients in the tiragolumab plus atezolizumab and chemotherapy group and 89 (39%) of 227 in the placebo and chemotherapy group; the most common serious adverse event was pneumonia (17 [7%] of 228 and 13 [6%] of 227). Treatment-related deaths occurred in six patients (3%) in the tiragolumab plus atezolizumab and chemotherapy group (immune-mediated lung disease, pneumonitis, cardiac arrest, gastrointestinal haemorrhage, hepatic failure, and bacterial pneumonia) and two (1%) in the placebo and chemotherapy group (gastrointestinal infection and death of unknown cause). No new safety signals were identified. Independent review facility-assessed progression-free survival and overall survival were significantly better in the tiragolumab plus atezolizumab and chemotherapy group compared with chemotherapy alone for unresectable locally advanced, unresectable recurrent, or metastatic oesophageal squamous cell carcinoma. These data support the rationale for exploring dual checkpoint inhibition added to chemotherapy for this group of patients with a high unmet need. F Hoffmann-La Roche–Genentech.

Lung metastasis is the primary cause of breast cancer-related mortality. Protein tyrosine phosphatases such as PTPRO are important in cancer progression. However, the role and underlying mechanisms of PTPRO in breast cancer lung metastasis are largely unknown. The function of PTPRO in breast cancer metastasis was examined in mice with ptpro deficiency driven by the PyMT promoter. The regulatory role of PTPRO in JAK2–YAP activation was tested in cell-based knockdown, overexpression and catalytic-dead mutation assays. Bioinformatics analyses and assays of human cancer specimens and mouse tumour samples were performed to investigate PTPRO-regulated pathways and functions. Ptpro deletion in MMTV- PyMT transgenic mice led to increased lung metastasis. Bioinformatics analyses and subsequent assays of human breast cancer specimens revealed a reverse correlation between PTPRO expression and JAK2–YAP pathway activity. Both in vitro and in vivo data demonstrated that PTPRO inactivates the JAK2–YAP pathway and diminishes the metastatic ability of breast cancer. Analysis of catalytic-dead PTPRO mutant breast cancer cells confirmed that functional PTPRO is a determinant of the activation of the JAK2–YAP pathway and the suppression of breast cancer metastasis. Data from patient, animal and cell-based models collectively demonstrated that PTPRO suppresses breast cancer lung metastasis by inhibiting JAK2–YAP dephosphorylation. Therefore, strengthening PTPRO or targeting PTPRO-mediated pathways could be potential strategies for inhibiting breast cancer lung metastasis.

Protein tyrosine phosphatase receptor-type O (PTPRO), a member of the PTP family, has garnered attention for its diagnostic and prognostic potential through the methylation of circulating tumor DNA (ctDNA). However, the utility of ctDNA has shown limited sensitivity and specificity, particularly in early-stage lung adenocarcinoma (LUAD). Given the enhanced stability of tumor-derived DNA in small extracellular vesicles (sEVs) from cancer cells, this research investigates the feasibility of using PTPRO methylation in saliva-derived sEVs as a non-invasive and easily accessible biomarker for the early detection of LUAD. To explore the relationship between PTPRO methylation and prognosis in early-stage LUAD, we conducted Kaplan-Meier survival analyses and assessed the methylation status of the PTPRO promoter using methylation-specific PCR (MSP) and q-MSP. Saliva samples were collected from 60 early-stage LUAD patients, 30 pneumonia patients, and 21 healthy controls, with isolation and characterization of salivary sEVs through transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and immunoblotting. Kaplan-Meier analysis revealed hypermethylation of PTPRO was linked to poorer overall survival in early-stage LUAD patients. PTPRO methylation was detected in salivary sEVs of 73.3% of early-stage LUAD patients, compared to only 35% in plasma sEVs. Receiver operating characteristic (ROC) analysis confirmed that PTPRO methylation in salivary sEVs effectively distinguished early-stage LUAD patients from both pneumonia patients and healthy individuals. This suggests that PTPRO hypermethylation is associated with adverse prognosis in early-stage LUAD. The detection of PTPRO methylation in salivary sEVs demonstrates high sensitivity and specificity, indicating its potential as an epigenetic biomarker for the non-invasive diagnosis of early-stage LUAD.

Background Breast cancer heterogeneity is not only involved by genetic and epigenetic alterations, but may also associated with the complexities at levels of protein modifications. Estrogen receptor (ER) positive breast cancer constitutes approximately 70% of all breast cancer cases, significantly impacting global female morbidity and mortality. Nuclear receptor co-activator 6 (NCOA6, also referred as AIB3) is a coregulator of sex hormone receptors as well as other transcription factors. Although the expression and functions of NCOA6 have been studied in breast, colon, lung, pancreatic cancers, and hepatocellular carcinoma, post-tranlational modification of NCOA6 is barely known. This study aims to study the NCOA6 phosphorylation, in particular at Serine 884, and its relevance to breast tumor aggressiveness and the prognostic significance. Methods We used bioinformatics and immunohistochemistry to detect NCOA6 expression and Ser884 phosphorylation in ER-positive breast cancer tissues. Cell proliferation, migration, and invasion were measured using CCK-8, transwell, and wound healing assays. Immunoblotting was used to detect protein levels and phosphorylation. Mouse xenograft models were established to evaluate tumor growth in vivo . Transcriptome and proteome analyses were performed to identify related signaling pathways. Results Total NCOA6 expression was not linked to cancer stage, subtype, or prognosis. However, phosphorylation at Ser884 was significantly increased in ER-positive breast cancer and associated with poorer outcomes, indicating its potential as an independent prognostic marker. Functional studies demonstrated that Ser884 phosphorylation promoted tumor cell proliferation, migration, and invasion in vitro and enhanced tumor growth in vivo . Mechanistically, ERK2 activation induced NCOA6 phosphorylation at Ser884, promoting epithelial-mesenchymal transition (EMT) and metastatic behavior. Only the phosphomimetic S884E mutant, not the non-phosphorylatable S884F mutant, restored migration and invasion in NCOA6-deficient cells. Transcriptomic and proteomic analyses further suggested that NCOA6 influences cell cycle, PI3K/AKT/mTOR signaling, and protein synthesis. Conclusion Phosphorylation of NCOA6 at Ser884 is markedly increased in ER-positive breast cancer, associates with aggressive clinicopathologic features, and portends poor prognosis. Functionally, enhanced NCOA6 phosphorylation promotes invasion and metastasis of ER-positive breast cancer cells. Collectively, these findings identify phospho-NCOA6 (Ser884) as a promising prognostic biomarker and potential therapeutic target, supporting more personalized management of ER-positive disease.

Esophageal squamous cell carcinoma (ESCC) is a deadly type of esophageal cancer. Programmed cell death (PCD) is an important pathway of cellular self-extermination and is closely involved in cancer progression. A detailed study of its mechanism may contribute to ESCC treatment. We obtained expression profiling data of ESCC patients from public databases and genes related to 12 types of PCD from previous studies. Hub genes in ESCC were screened from PCD-related genes applying differential expression analysis, machine learning analysis, linear support vector machine (SVM), random forest and Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis. In addition, based on the HTFtarget and TargetScan databases, transcription factors (TFs) and miRNAs interacting with the hub genes were selected. The relationship between hub genes and immune cells were analyzed using the CIBERSORT algorithm. Finally, to verify the potential impact of the screened hub genes on ESCC occurrence and development, a series of cell experiments were conducted. We screened 149 PCD-related DEGs, of which five DEGs ( , , , , and ) were identified as the hub genes of ESCC. The area under the curve (AUC) of receiver operating characteristic (ROC) curve of the integrated model developed using the hub genes reached 0.997, showing a noticeably high diagnostic accuracy. The number of TFs and miRNAs regulating hub genes was 105 and 22, respectively. , and were overexpressed in cancer tissues and cells of ESCC. Notably, knockdown suppressed ECSS cell migration and invasion and altered the expression of important apoptotic and survival proteins. This study identified significant molecules with promising accuracy for the diagnosis of ESCC, which may provide a new perspective and experimental basis for ESCC research.