ObjectiveTo compare the patterns of lymph node metastasis (LNM) in patients with thoracic esophageal squamous cell carcinoma (TESCC) treated with neoadjuvant immunochemotherapy (nICT) versus neoadjuvant chemotherapy (nCT) alone and its impact on prognosis and potential clinical implications.MethodsA single-center retrospective cohort study was conducted on 441 patients with locally advanced TESCC who underwent nCT (n=179) or nICT (n=262) followed by esophagectomy. LNM patterns were analyzed according to the Japanese Classification of Esophageal Cancer (12th Edition), using metrics including lymph node ratio (LNR), lymph node metastasis rate and actual lymph node metastasis rate for specific stations. Postoperative recurrence patterns, overall survival (OS), and event-free survival (EFS) were also evaluated.ResultsCompared with nCT, nICT achieved a significantly higher pathological complete response (pCR) rate (22.1% vs. 6.7%, p < 0.001) and a lower metastatic lymph node ratio (LNR) (3.5% vs 6.2%, p < 0.001). Although the overall LNM rate was similar between groups, nICT demonstrated reduced lymph node involvement in several key station lymph nodes, particularly level 7 (along the left gastric artery), with lower the lymph node metastasis rate (LNMR2) (7.6% vs. 14.5%, p = 0.020) and the actual metastasis rate (LNMR3) (8.4% vs. 16.8%, p = 0.012). The overall recurrence/metastasis rate was significantly lower in the nICT group (36.2% vs. 56.8%, p < 0.001), with a notable reduction of recurrence at the anastomotic site. In multivariable analyses, nICT independently predicted lower recurrence risk (adjusted OR = 0.55, p = 0.013) and improved EFS (HR = 0.65, p = 0.001) while OS was not statistically different between groups.ConclusionIn comparison to nCT alone, nICT was significantly associated with deeper pathological response, lower LNM burden, and reduced postoperative recurrence in TESCC.

Wnt signaling is a highly conserved pathway that regulates cell proliferation, differentiation, apoptosis and stem cell self-renewal, which has implications for embryonic development and tumorigenesis. We investigated the potential role of candidate single nucleotide polymorphisms (SNPs) of Wnt signaling pathway genes with computational evidence of regulatory potential on lung cancer in Chinese Han patients. The case-control study included 1,143 diagnosed primary lung cancer patients and 1,172 healthy controls. It was identified that Wnt2 rs4730775, Axin1 rs1981492 and Dvl2 rs222851 were associated with increased risk of lung cancer (adjusted Odds Ratio [ORadj] = 1.227, 95% confidence interval [CI] = 1.020-1.477; ORadj = 1.460, 95% CI = 1.019-2.090; ORadj = 1.477, 95% CI = 1.200-1.819, respectively). Dvl2 rs222851 was associated with a noticeably increased risk of lung cancer using dominant model by multi-classification logistic regression analysis (ORadj = 1.437, 95% CI = 1.178-1.754). Meanwhile, it enhanced the predictive ability of lung cancer incidence with the area under the Receiver Operating Characteristic Curve (AUROC) increased to 0.742 (95% CI = 0.721-0.762). Additionally, the crossover analysis revealed that Dvl2 rs222851 risk genotypes along with cooking oil fume exposure increased lung cancer risk by 1.514-fold (ORadj = 2.514, 95% CI = 1.647-3.839). There was positive multiplicative interaction between rs222851 and cooking oil fume exposure (ORadj = 1.174, 95% CI = 1.055-1.306). Our findings indicated that the genetic mutation of Wnt2 rs4730775, Axin1 rs1981492 and Dvl2 rs222851 on Wnt signaling pathway could promote the occurrence of lung cancer in Chinese Han population. Additionally, the Dvl2 rs222851 variant was significantly associated with exposure to cooking oil fumes.

Photoimmunotherapy has emerged as a promising modality in cancer treatment, but its effectiveness is limited by inadequate photoagent delivery and inflammation-induced immunosuppression. Herein, we developed an NIR-II-emitting mucosa-penetrating nanoplatform (LMPNCXB) for image-guided bladder cancer therapy. This nanoplatform integrates celecoxib (CXB), a cyclooxygenase-2 (COX-2) inhibitor, with an aggregation-induced emission luminogen (DCTBT) in a single optimized formulation. The positively charged surface formed by chitosan and cationic lipids enhances the nanoplatform's mucosal adhesion and penetration. Notably, owing to its pH- and ROS-responsive properties, it can selectively accumulate in tumors. The incorporated DCTBT serves both as an NIR-II imaging agent for precise tumor visualization and as an efficient photothermal converter, allowing targeted tumor ablation while simultaneously promoting the release of tumor-associated antigens. Simultaneously, the released CXB downregulates COX-2 expression, decreasing inflammation-induced immunosuppression to improve photoimmunotherapy. By reducing off-target drug accumulation in healthy tissues, this mucosal-administration nanoplatform presents an efficient, precise, and low-toxicity strategy for bladder cancer therapy.

BACKGROUND:Benign airway stenosis (BAS) involves progressive pathological narrowing of the trachea and main bronchi, causing clinically significant respiratory impairment that can advance to life-threatening obstruction. While fibrosis arises from dysregulated immune-stromal crosstalk, the specific cellular and molecular drivers of BAS remain poorly understood. METHODS:We conducted single-cell RNA sequencing on clinical specimens representing the BAS spectrum normal airway, granulation tissue, and fibroproliferative tissue. Integrated bioinformatic analyses delineated cellular heterogeneity, intercellular communication, and differentiation trajectories. Spatial validation of key subsets was performed using multiplex immunofluorescence. Functional assessment of the PROS1-AXL axis involved treating primary human airway granulation fibroblasts (PHAGF) isolated from BAS patients with either conditioned medium from RANKL-stimulated THP-1 macrophages or recombinant PROS1, followed by inhibition with the AXL-specific antagonist R428. In parallel, an in vivo mouse model of BAS was used to evaluate the therapeutic efficacy of R428. RESULTS:Transcriptomic analysis revealed substantial remodeling of the BAS microenvironment, marked by epithelial depletion and expansion of stromal and immune compartments. We identified a novel macrophage subset co-expressing CTSK and SLC9B2, specifically enriched in granulation tissue. Communication analysis demonstrated selective PROS1-AXL signaling between CTSK+ macrophages and CD82+ fibroblasts. Pseudotemporal analysis positioned this crosstalk upstream of myofibroblast differentiation. Multiplex immunofluorescence confirmed CTSK+ macrophage localization in human BAS granulation tissue. In vitro, conditioned medium from RANKL-primed THP-1 macrophages promoted fibroblast activation in PHAGF cells through the PROS1-AXL axis, an effect that was attenuated by AXL inhibition with R428. Furthermore, Western blot analysis revealed that PROS1-AXL signaling activated the AKT/GSK3β pathway in PHAGF cells. In vivo, systemic administration of R428 in a BAS mouse model significantly reduced fibrotic remodeling, as evidenced by decreased granulation tissue hyperplasia, collagen deposition, and improved survival compared to vehicle-treated controls. Furthermore, TNFSF11 on CD82+ fibroblasts may bind TNFRSF11A on CTSK+ macrophage precursors to drive their differentiation. CONCLUSION:This work defines a pro-fibrotic cellular module in BAS CTSK+ macrophages and CD82+ fibroblasts interacting via PROS1-AXL and establishes a rationale for targeting this pathway, supported by both patient-relevant primary cell and in vivo evidence, to disrupt fibrosis and mitigate recurrence.

Small extracellular vesicles (sEVs) hold immense potential for liquid biopsy given the wealth of biological information they carry. Currently, the clinical application of these methods is limited due to their low abundance and the complexities associated with traditional isolation techniques. To address this, we developed a strategy integrating cholesterol-mediated capture with a Self-Protected DNAzyme Walker for the rapid and simultaneous specific isolation and quantification of small extracellular vesicles (sEVs). Upon specific binding to CD63, the blocker strand is released, which activates the DNAzyme catalytic core, leading to substrate cleavage, which triggers the specific release of sEVs from magnetic beads and the generation of a fluorescent signal. Importantly, the circular DNA Shield design provides remarkable stability to the system by safeguarding the DNAzyme core from nuclease degradation. Furthermore, the cyclic cleavage mechanism allows for highly sensitive detection, achieving a limit of detection (LOD) as low as 361 particles per μL. In addition, by leveraging the lipid bilayer structure for sEV enrichment, this strategy effectively eliminates interference from free proteins. Furthermore, the clinical feasibility of this assay was validated by successfully distinguishing Stage I breast cancer patients from healthy individuals with high statistical significance (p < 0.001), highlighting its promise for early cancer diagnosis. This work presents a robust paradigm for sEV analysis and lays a solid foundation for their downstream biomedical applications.

Lipid metabolic reprogramming is increasingly recognized as a critical feature of prostate cancer progression, but the lipid metabolism-related genes that remain continuously dysregulated from normal tissue to primary tumor and metastatic disease have not been systematically characterized, and their biological and prognostic relevance remains incompletely understood. To identify lipid metabolism-related genes associated with continuous prostate cancer progression and develop a prognostic signature for survival stratification. Clinical prostate cancer specimens and a high-fat diet (HFD)-driven RM-1 tumor model were first used to evaluate lipid metabolic alterations in vivo. GSE6919 transcriptomic data were used to identify genes shared between the Normal–Primary and Primary–Metastatic transitions. These genes were intersected with a curated lipid metabolism-related gene set, followed by GO and KEGG enrichment analyses. TCGA prostate adenocarcinoma expression and clinical data were used for LASSO regression to construct a prognostic model. The four core genes were further evaluated by clinicopathological correlation analysis, protein- and transcript-level validation in clinical tissues and prostate cancer cell lines, and functional assays under oleic acid-induced lipid stress. Immune infiltration analysis, ssGSEA, and nomogram analysis were performed to assess the biological and clinical relevance of the model. Clinical tissues showed increased PLIN3 expression, and HFD feeding promoted tumor growth and reinforced lipid metabolic alterations in vivo. A total of 44 lipid metabolism-related genes were identified as continuously dysregulated during prostate cancer progression. These genes were mainly enriched in fatty acid metabolism, lipid catabolism, peroxisome, lipid droplet, glycolysis/gluconeogenesis, arachidonic acid metabolism, and PPAR signaling. Eight genes were significantly associated with overall survival in TCGA, and a four-gene signature comprising ALDH3A2, ENO2, PPP1CB, and PTGIS was established. This model effectively stratified patients into high- and low-risk groups with significantly different survival outcomes. The risk score was positively associated with clinical T stage and Gleason score. The four core genes were also associated with lipid metabolic enzymes, immune infiltration patterns, and multiple metabolism-related pathways. Protein- and transcript-level validation in clinical tissues and prostate cancer cell lines supported the biological relevance of the signature, although PTGIS showed a more context-dependent pattern. Functionally, silencing ENO2 reduced oleic acid-induced lipid peroxidation, whereas silencing PPP1CB enhanced it, while ALDH3A2 showed a more context-dependent effect. A nomogram integrating the risk score with clinical variables improved individualized survival prediction. We identified lipid metabolism-related genes continuously dysregulated during prostate cancer progression and established a four-gene prognostic signature with potential value for survival prediction and risk assessment. These findings highlight lipid metabolic rewiring as an important component of prostate cancer evolution and provide candidate biomarkers for future mechanistic and translational studies.

Acute monocytic leukemia (AML-M5) is a type of acute myeloid leukemia, characterized by a dominance of monocytes in the bone marrow and peripheral blood. AML-M5 exhibits a poor prognosis compared to other AML subtypes. Despite clinical recognition, current research on AML-M5 remains relatively limited, and its underlying pathogenic mechanisms are not yet fully understood. In this study, we uncover a distinct and heightened expression of CBX4, a core component of PRC1, in the peripheral blood of individuals diagnosed with AML-M5. By generating cbx4 overexpression transgenic and deleted mutant zebrafish lines, we observe elevated cbx4 expression in monocyte/macrophage, selectively modulating their production during zebrafish hematopoiesis. Notably, aging zebrafish with cbx4 overexpression exhibit a progression to AML-M5-like hematopoiesis. Further mechanistic analyses reveal that Cbx4 regulates the fate of monocyte/macrophage lineage by suppressing runx1 expression. This suppression is achieved through the recruitment of HDAC to the runx1 promoter via cbx4, resulting in the down-regulation of the H3K27 acetylation level of runx1. These findings offer novel insights, providing potential avenues for risk assessment and molecular diagnosis of AML-M5 leukemia. Moreover, CBX4 emerges as a promising target for the diagnosis and treatment of AML-M5 leukemia.

RUNX3 acts as a tumor suppressor gene in non-small-cell lung cancer (NSCLC), yet its specific biological mechanism is still unclear. This study aimed to uncover tumor microenvironment (TME) changes in NSCLC with varying RUNX3 expression statuses through single-cell RNA sequencing. In total, seven patients with NSCLC with detailed pathological data were involved, with three both paracancerous and cancerous tissue samples. After sequencing, the “Seurat” package was used to analyze differentially expressed genes, annotate cell clusters with marker genes, and compare cell proportion differences at different RUNX3 expression levels. Observed-over-expected cell number ratios (Ro/e) assessed cell type enrichment among three pathological types. Immunohistochemical staining of RUNX3 categorized three patients into the RUNX3-negative group (RUNX3_Neg) and four into the RUNX3 positive group (RUNX3_Pos). All cells were classified into 13 types based on marker genes. Ro/e results showed fibroblasts were the only enriched cell type in RUNX3_Pos cancer tissue, while club cells, ciliated cells, and so on were enriched in RUNX3_Neg cancer tissue. RUNX3_Neg tissues were more likely to accumulate certain immune cells compared with RUNX3_Pos tissues. Ro/e also indicated RUNX3_Neg cancer tissues were more prone to macrophage depletion, while RUNX3_Pos tissues were more prone to macrophage enrichment. Through single-cell sequencing, our study found that RUNX3 expression status is closely related to NSCLC TME. Mononuclear phagocytes may be an important target cell population for RUNX3 to change TME.

The role of Thiol Methyltransferase 1A (TMT1A) in lung adenocarcinoma (LUAD) progression and the immune microenvironment remains unclear. Analysis of clinical samples and public databases revealed significantly lower TMT1A expression in tumorous LUAD samples compared to non-neoplastic counterparts. Cox regression analysis confirmed TMT1A as an independent prognostic factor for LUAD. Phenotypically, functional assays demonstrated that TMT1A expression inhibited LUAD cell proliferation and migration. Furthermore, single cell transcriptome sequencing analysis showed that TMT1A expression was positively correlated with the immune cells, especially macrophages. Mechanistically, high TMT1A expression was found to inhibit M2 macrophage polarization and downregulate PD-L1 expression in LUAD cells. In co-culture experiments involving LUAD cells and T cells, TMT1A knockdown suppressed T cell activation and reduced IFN-γ secretion. These findings were further validated by in vivo experiments, where TMT1A expression was found to promote CD8+ T cell infiltration in LUAD. These findings demonstrated tumor-suppressive functions coupled with its immunomodulatory capacity position TMT1A as a promising therapeutic target for LUAD treatment.

Derlin-3 has been implicated as an essential element in the degradation of misfolded lumenal glycoproteins induced by endoplasmic reticulum (ER) stress. However, its potential biomechanisms in the tumor microenvironment (TME) of lung adenocarcinoma (LUAD) remains to be elucidated. In the present study, we found that Derlin-3 was predominantly elevated in LUAD tissues, and could predict worse prognosis of LUAD patients. ScRNA-seq analysis indicated that Derlin-3 was mainly enriched in B lymphocytes in the TME, especially in plasma cells. Moreover, Derlin-3 may be involved in ER stress and IgG4 secretion in plasma cells by targeting Hrd1/p38/PRDM1 pathway. While the aberrant IgG4 production may be an essential driver of the polarization of macrophages towards the M2 phenotype. Additionally, downregulation of Derlin-3 could inhibit plasma cells infiltration and M2 macrophage polarization in vivo. Our results indicated that Derlin-3 could shape TME via ER stress to harness immune function, which might serve as a promising immunotherapeutic target in LUAD.

Cancer remains a great danger for health and well-being as well as a challenge for the sustainability of Health Systems worldwide. At the same time, tumor theranostics are hampered by limitations in imaging sensitivity, inadequate specificity, side effects and the emergence of therapeutic resistance. Tumor endogenous-activatable theranostic probes have emerged as critical tools for advancing precision diagnostics and targeted treatment of aggressive malignancies. In this study, we developed an endogenous stimuli-derived self-assembled DNA tetrahedron (MESH) nanodevice for simultaneous tumor visualization and activatable mitochondrial interference therapy. The DNA tetrahedron precisely recognized cancer cells via the Mucin-1 (MUC1) aptamer, and tumor-derived microRNA activated a strand displacement cascade amplification reaction to enable specifically and sensitively fluorescence imaging of malignant lesions. Concurrently, the in situ self-assembly process of DNA tetrahedron was initiated to form a DNA network under the stimulation of microRNA in cytoplasm. The self-assembled DNA network could selectively localize to mitochondria, acting as a polyanionic barrier that disrupts mitochondrial function and induces apoptosis. This endogenous tumor microenvironment-regulated morphological transformation between biocompatible DNA tetrahedral and DNA network with suborganelle interference functions might address the side effects and resistance issues of tumor treatment. The MESH provided a novel strategy for cancer imaging and mitochondrial manipulation through endogenous molecular-guided assembly with potential applications in theranostics.

Metastasis is the primary cause for treatment failure and poor prognosis in patients with triple-negative breast cancer (TNBC). Macroautophagy/autophagy plays a crucial role in tumor growth and metastasis. Genetic or epigenetic regulation of autophagy-related factors alters autophagy levels, which subsequently promotes cancer progression and affects the therapeutic effectiveness. However, the molecular basis for the transcriptional and epigenetic regulation of autophagy in TNBC progression is poorly understood. In this study, we reveal the histone methyltransferase NSD2/WHSC1 (nuclear receptor binding SET domain protein 2) as a novel epigenetic regulator of autophagy in TNBC progression. We demonstrate that the expression of NSD2 is significantly upregulated in TNBC cells and high NSD2 expression is correlated with poor TNBC survival. Elevated expression of NSD2 significantly promotes TNBC metastasis in multiple TNBC models. Mechanistically, ULK1 (unc-51 like autophagy activating kinase 1) is identified as a novel target of NSD2 and NSD2-mediated histone H3K36me2 methylation directly activates ULK1 transcription in TNBC cells. Notably, NSD2-induced ULK1 expression facilitates autophagosome maturation and increases autophagic flux, thus promoting autophagy-related malignancy progression in TNBC. Furthermore, pharmacological inhibition of NSD2 using MS159 and MCTP-39 significantly suppresses TNBC autophagy, growth, and metastasis both in vivo and in vitro. In conclusion, our findings demonstrate a pivotal epigenetic role for the NSD2-H3K36me2 axis in regulating ULK1 expression and identify a novel NSD2-ULK1-autophagy signaling axis in the promotion of TNBC progression, suggesting that NSD2 inhibition may be an effective treatment strategy for TNBC.Abbreviations: CDH2/N-cadherin: cadherin 2; ChIP: chromatin immunoprecipitation; EMT: epithelial-mesenchymal transition; ESR: estrogen receptor; FN1: fibronectin 1; GEPIA: Gene Expression Profiling Interactive Analysis; H3K36me2: di-methylation at lysine 36 of histone 3; H&E: hematoxylin and eosin; HDM: histone demethylase; HMT: histone methyltransferase; HIF1A/HIF-1α: hypoxia inducible factor 1 subunit alpha; IF: Immunofluorescence; IHC: Immunohistochemistry; NSD: nuclear receptor binding SET domain protein; PGR: progesterone receptor; qRT-PCR: quantitative RT-PCR; TCGA: The Cancer Genome Atlas; TNBC: triple-negative breast cancer; TSS: transcription start site; ULK1: unc-51 like autophagy activating kinase 1.

A finely engineered NIR AIE probe, namely TTTVPHE, was synthesized with dithieno[2,3-b:2',3'-d]thiophene to bridge triphenylamine and pyridinium units for cell membrane-targeted cancer phototheranostics. TTTVPHE has significant advantages such as strong cell membrane binding affinity, NIR-I/II emission, superior AIE characteristics, and excellent type I/II ROS generation ability.

Heterobimetallic nanozymes hold great promising in cancer catalytic therapy by leveraging dual-active sites that are electronically coupled. However, their therapeutic potential is limited by high inherent complexity and lack of clarity regarding their electron conformation. In this study, we developed a ligand coordination field engineering strategy to construct a cyano-bridged bimetallic nanozyme Cu2[Fe(CN)6] (SANE) with a well-defined electronic configuration for cancer catalytic-immunotherapy. Density functional theory (DFT) calculations revealed that cyano groups, acting as strong-field bridging ligands, could form an electron delocalization network. This network, driven by electronegativity gradient of the Cu (d9) and Fe (d6) bimetallic active centers, induces synergistic distortion of d-band energy levels, which in turn enhances electron transfer and significantly improves catalytic efficiency. Furthermore, the cyano-bridging, stabilizes the structure through a strong coordination field inhibiting metal aggregation, and allowing Cu to exhibit a single-atom distribution. This further strengthens SANE catalytic therapy ability. Biomimetic modification of SANE with immunogenic tumor exosomes (iEV) enhances biocompatibility, and provides efficient Peroxidase (POD)-like and Glutathione oxidase (GSHox)-like enzymatic activities within the tumor microenvironment achieving a catalytic-immune synergistic effect. This study provides a comprehensive framework to design heterobimetallic nanozyme with ideal catalytic structure from bimetallic active sites to bridged-ligand, opening a new avenue for precisely regulating of electronic configuration in catalytic-immunotherapeutic nanoplatform.

This study aimed to investigate the efficacy, safety, and predictors of camrelizumab combined with carboplatin and nab-paclitaxel as first-line setting for patients with extensive-stage small-cell lung cancer (ES-SCLC). Camrelizumab plus carboplatin and nab-paclitaxel were administrated every 3 weeks for four to six cycles, followed by maintenance camrelizumab until intolerable toxicity or disease progression. The primary endpoint was 6-month progression-free survival (PFS) rate and secondary endpoints were objective response rate (ORR), disease control rate (DCR), PFS, overall survival (OS), and safety. We conducted the whole-exome and transcriptomic sequencing on available tumor samples to explore the potential predictive biomarkers. A total of 60 patients were included. Primary endpoint was met with 6-month PFS rate of 52.2%. The median PFS and OS were 7.1 and 18.1 months, respectively. The confirmed ORR and DCR were 73.3% and 93.3%, respectively. No unexpected adverse events were observed. Exploratory analysis showed that MUC17 alterations or high NEUROG1 expression were correlated with markedly shorter PFS and OS. Deeper investigation of transcriptomic data reveals two subsets with distinct immune features and therapeutic vulnerabilities. Collectively, this trial suggested that camrelizumab plus carboplatin and nab-paclitaxel might be an alternative first-line setting for ES-SCLC. Integration of multiomic data could highlight the complex mechanisms underlying chemo-immunotherapy responses.

Lung cancer's metastatic propensity and recurrence prevalence necessitate innovative immunotherapy strategies beyond conventional single-mode regulation. We engineered low-capacity turmeric-derived extracellular vesicles (TEVs) that integrated with zeolitic imidazolate framework-8 (ZIF-8) to construct an "all-in-one" nanoagent, addressing both high drug loading nanocarriers production and immunologically cold tumor challenges. The system co-delivered chlorin e6 (Ce6) and PD-L1 siRNA, while exploited TEVs' inherent curcumin for Wnt/β-catenin pathway inhibition. Ce6-mediated photodynamic therapy (PDT) induced immunogenic cell death (ICD), releasing damage associated molecular patterns (DAMPs) to activate antigen-presenting cells (APCs). Compared with control groups, artificial intelligence model confirmed the role of curcumin in enhancing immune infiltration by 6.1-fold. PD-L1 siRNA synergistically downregulates the checkpoint expression with a 66 % reduction in vivo to prevent the immune escape. This coordinated strategy achieved full-cycle immunomodulation: (1) ICD initiated antigens release, (2) Wnt/β-catenin pathway inhibition drived T cell infiltration, and (3) PD-L1 blockade receded the immune escape. In vivo results demonstrated that 64 % primary tumor suppression and 81 % metastasis reduction versus monotherapy groups. The ZIF-8@TEV hybrid platform exhibited 12.8 % payload loading efficiency, surpassing liposomal carriers by 4.7-fold. This study established a scalable nanoengineering approach to transform immunosuppressive tumors into immunotherapy-responsive targets through a full-cycle immune coordination.

The sequences of the siRNAs are listed in Supplementary Table S1. And the sequences of the primers, ChIP primers and MeRIP primers used are listed in Supplementary Table S2.