The stringent regulation of intrahepatic metastases is essential for improving survival outcomes in patients with hepatocellular carcinoma (HCC). This study investigated the impact of gut microbiota on intrahepatic metastasis of HCC and evaluated the therapeutic potential of healthy fecal microbiota transplantation (FMT). Dysregulation of the gut microbiota, characterized by a significant reduction in the abundance of beneficial bacteria, such as Anaerotruncus colihominis and Dysosmobacter welbionis, was observed in patients with intrahepatic metastatic HCC. A human flora-associated (HFA) intrahepatic metastatic HCC mouse model was successfully established through consecutive 4 weeks of human-mouse FMT. Dysregulation of gut microbiota promoted intrahepatic metastasis in the mouse model, primarily by enhancing neutrophil-mediated inflammatory responses and lead to excessive formation of neutrophil extracellular traps (NETs). Consequently, it promoted tumor vascular growth and tissue necrosis, resulting in intrahepatic metastasis of HCC. Notably, FMT from healthy donors mitigated these pathological processes. This study elucidated the role and mechanism of dysregulated gut microbiota in promoting intrahepatic metastasis of HCC. Healthy FMT emerges as a promising novel therapeutic strategy for preventing and treating intrahepatic metastasis of HCC.

Neutrophils play a complex role in cancer biology, can contributing to tumor progression and immune defense. Neutrophil extracellular traps (NETs) have emerged as key modulators within the tumor microenvironment. Herein, the association between molecular classification, histological grade, necrosis, tumor-infiltrating neutrophils, and NETs was assessed in 19 canine mammary malignant tumors. Immunohistochemistry using citrullinated histone-3 (cith3) and myeloperoxidase (MPO) antibodies were used to detect NETs. A fading and re-staining method was applied on the same sections. NETs were scored based on the presence of cith3 positive areas and compared with tumor grade. The neutrophil score numerically increased as the tumor grade increased. The NET score was slightly higher in grade I carcinomas compared to carcinomas with other grades. On contrary, the necrosis score was also higher in grade II and III tumors than grade I tumors. A low but non-significant negative correlation existed between tumor grade and NET score (r = -0.219). No statistically significant associations between the tumor markers (ER, PR, HER2) and molecular subtypes with tumor grade, NET score, neutrophil count, and necrosis. In this study, the presence of NETs in canine malignant mammary tumor of different histological subtypes and grades was reported. Preliminary evidence was gathered that NETs are negatively correlated with tumor grade, suggesting their potential role in prognostication.

Prostate cancer remains a substantial health challenge, with >375,000 annual deaths amongst men worldwide. Most prostate cancer-related deaths are attributable to the development of resistance to standard-of-care treatments. Characterization of the diverse and complex surfaceome of treatment-resistant prostate cancer, combined with advances in drug development that leverage cell-surface proteins to enhance drug delivery or activate the immune system, have provided novel therapeutic opportunities to target advanced prostate cancer. The prostate cancer surfaceome, including proteins such as prostate-specific membrane antigen (PSMA), B7-H3, six transmembrane epithelial antigen of the prostate 1 (STEAP1), delta-like ligand 3 (DLL3), trophoblastic cell-surface antigen 2 (TROP2), prostate stem cell antigen (PSCA), HER3, CD46 and CD36, can be exploited as therapeutic targets, as regulatory mechanisms might contribute to the heterogeneity of expression of these proteins and subsequently affect treatment response and resistance. Specific treatment strategies targeting the surfaceome are in clinical development, including radionuclides, antibody-drug conjugates, T cell engagers and chimeric antigen receptor (CAR) T cells. Ultimately, biomarker development and clinical implementation of these agents will be informed and refined by further understanding of the biology of various targets; the target specificity and sensitivity of different agents; and off-target and toxic effects associated with these agents. Understanding the dynamic nature of cell-surface targets and non-overlapping expression patterns might also lead to future combinational strategies.

Tumors are structures of high complexity. Plurality of their structural and functional components - heterogeneity, diversity, directionality, interdependence and integration of signaling pathways - seem to follow isolated local rules, whereby a superordinate structure remains largely unknown. Understanding the complexity of cancer is the mainstay in finding determinants and developing effective therapies. Interleukin 8 (IL-8) is a potent pro-inflammatory chemokine that is significantly elevated in many different tumor entities. In contrast to its initially postulated anti-tumor properties, an increasing number of studies have been published in recent years linking this chemokine with tumor-promoting features and poor prognosis. This review summarizes the current state and diversity of the role of IL-8 in the development of cancer.

The neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) have been confirmed to be related to the clinicopathological features and prognosis of colorectal cancer (CRC) patients. However, the results have been inconsistent, and few studies have focused on a specific point in time during surgery and dynamic changes prior to and after surgery.

We conducted a retrospective analysis of 349 CRC patients and explored the value of NLR, PLR and their dynamic changes in predicting clinicopathological variables and prognosis in CRC.

Preoperative NLR (Pre-NLR) was correlated with CEA, CA199 levels, tumor location and tumor stage (P=0.041, P=0.002, P=0.001 and P=0.012, respectively), whereas postoperative NLR (post-NLR) was relevant to age, sex, CA125 levels and T stage significantly (P=0.032, P=0.002, P=0.026, P=0.019, respectively). When comparing post- and pre-NLR values, there was a positive connection between increases in NLR and BMI, tumor location, T stage, and tumor stage (P=0.034, P=0.005, P=0.023, P=0.023, respectively). In addition, Preoperative PLR (pre-PLR) was correlated with sex, smoke and drink history, CEA and CA199 levels, tumor location, T stage and tumor stage (P=0.006, P=0.037, P=0.040, P=0.006, P=0.005, P<0.001, P=0.007, P=0.003 respectively), while postoperativePLR (post-PLR) was only associated with tumor location (P=0.010). Increases in PLR were significantly related to sex, smoking history, tumor location and differentiation (P=0.001, P=0.002, P<0.001, P=0.034, respectively). Patients with CRC who had a high post-PLR experienced significantly shorter relapse-free survival (RFS) compared to other patients (HR 0.607 (0.381-0.968), P=0.036). Furthermore, this high post-PLR has tendency association with shorter overall survival (OS) (HR 0.596 (0.338-1.050), P=0.076).

These findings suggest that levels and changes in NLR/PLR are associated with several unfavorable clinicopathological features in CRC patients. Furthermore, patients with high levels of post-PLR exhibit a worse prognosis.

Pancreatic cancer is renowned for its aggressive nature and dismal prognosis, with the majority of patients diagnosed at an advanced stage. The prognosis for patients with pancreatic cancer can be improved by early diagnosis and effective treatment. Circulating cell-free DNA (cfDNA) has emerged as a promising biomarker for the early diagnosis and monitoring of pancreatic cancer. This research presents a review of circulating cell-free DNA essential role in the early diagnosis and immunotherapy of pancreatic cancer. The detection methods of cfDNA, its potential as a diagnostic biomarker, and the latest research progress in cfDNA-based immunotherapy are discussed. The findings suggest that cfDNA plays a vital role in the early detection and personalised treatment of pancreatic cancer, holding great promise for improving patient outcomes.

Gastric cancer (GC) is a highly aggressive malignancy associated with poor prognosis, particularly in its advanced stages. Neutrophil extracellular traps (NETs) have been implicated in cancer progression and immune therapy responses; however, the role of NETs-related long non-coding RNAs (lncRNAs) in GC remains poorly understood. This study used data from the Cancer Genome Atlas (TCGA) and previous research to identify NETs-related lncRNAs in GC. A prognostic signature comprising four NETs-related lncRNAs (NlncSig) was developed and validated, serving as a predictor for patient survival and response to immunotherapy. The NlncSig was correlated with poorer outcomes in high-risk patients and demonstrated that those with lower risk scores exhibited more favorable responses to immunotherapy. In vitro experiments confirmed that LINC01150 enhances GC cell proliferation, migration, and invasion. This robust NlncSig provides a reliable tool for predicting survival and immune characteristics in GC, with the potential to guide personalized therapeutic approaches and improve patient care.

Brain metastases are the most commonly diagnosed type of central nervous system tumor, yet the mechanisms of their occurrence are still widely unknown. Lung cancer, breast cancer, and melanoma are the most common etiologies, but renal and colorectal cancers have also been described as metastasizing to the brain. Regardless of their origin, there are common mechanisms for progression to all types of brain metastases, such as the creation of a suitable tumor microenvironment in the brain, priming of tumor cells, adaptations to survive spreading in lymphatic and blood vessels, and development of mechanisms to penetrate the blood-brain barrier. However, there are complex genetic and molecular interactions that are specific to every type of primary tumor, making the understanding of the metastatic progression of tumors to the brain a challenging field of study. In this review, we aim to summarize current knowledge on the pathophysiology of brain metastases, from specific genetic characteristics of commonly metastatic tumors to the molecular and cellular mechanisms involved in progression to the central nervous system. We also briefly discuss current challenges in targeted therapies for brain metastases and how there is still a gap in knowledge that needs to be overcome to improve patient outcomes.

The success of disseminating cancer cells (DTCs) at specific metastatic sites is influenced by several metabolic factors. Even before DTCs arrival, metabolic conditioning from the primary tumor participates in creating a favorable premetastatic niche at distant organs. In addition, DTCs adjust their metabolism to better survive along the metastatic journey and successfully colonize their ultimate destination. However, the idea that the environment of the target organs may metabolically impact the metastatic fate is often underestimated. Here, we review the coexistence of two distinct strategies by which cancer cells shape and/or adapt to the metabolic profile of colonized tissues, ultimately creating a proper soil for their seeding and proliferation.

Neutrophils are pivotal in the immune system and have been recognized as significant contributors to cancer development and progression. These cells undergo metabolic reprogramming in response to various stimulus, including infections, diseases, and the tumor microenvironment (TME). Under normal conditions, neutrophils primarily rely on aerobic glucose metabolism for energy production. However, within the TME featured by hypoxic and nutrient-deprived conditions, they shift to altered anaerobic glycolysis, lipid metabolism, mitochondrial metabolism and amino acid metabolism to perform their immunosuppressive functions and facilitate tumor progression. Targeting neutrophils within the TME is a promising therapeutic approach. Yet, focusing on their metabolic pathways presents a novel strategy to enhance cancer immunotherapy. This review synthesizes the current understanding of neutrophil metabolic reprogramming in the TME, with an emphasis on the underlying molecular mechanisms and signaling pathways. Studying neutrophil metabolism in the TME poses challenges, such as their short lifespan and the metabolic complexity of the environment, necessitating the development of advanced research methodologies. This review also discusses emerging solutions to these challenges. In conclusion, given their integral role in the TME, targeting the metabolic pathways of neutrophils could offer a promising avenue for cancer therapy.

Neutrophils, the most abundant myeloid cells in human peripheral blood, serve as the first defense line against infection and are also significantly involved in the initiation and progression of cancer. In colorectal cancer (CRC), neutrophils exhibit a dual function by promoting tumor events and exerting antitumor activity, which is related to the heterogeneity of neutrophils. The neutrophil extracellular traps (NETs), gut microbiota, and various cells within the tumor microenvironment (TME) are involved in shaping the heterogeneous function of neutrophils. This article provides an updated overview of the complex functions and underlying mechanisms of neutrophils in CRC and their pivotal role in guiding prognosis assessment and therapeutic strategies, aiming to offer novel insights into neutrophil-associated treatment approaches for CRC.

Phagocytic clearance by macrophages represents a critical immune surveillance mechanism in cancer liver metastasis. Neutrophils, the most abundant immune cells encountered by cancer cells in circulation, play key roles in metastasis through neutrophil extracellular traps (NETs). Although NETs promote macrophage phagocytosis during infection, whether they regulate phagocytosis during cancer metastasis is unknown. The present study aimed to explore the roles of NETs in regulating macrophage phagocytosis during the seeding process of liver metastasis and the mechanisms underlying the roles.

A lipopolysaccharide-induced NET model was applied to study the role of NETs on colorectal cancer (CRC) liver metastasis. The neutrophils isolated from human peripheral blood were stimulated with PMA to release NETs, which were collected and added to the cultures of different CRC cell lines for in vitro studies. Macrophage phagocytosis was assessed with flow cytometry in vitro and in vivo. RNA-seq and microRNA array analyses were performed to identify key pathways regulated by NETs and downstream key molecules. The macrophage phenotypes were evaluated using immunohistochemistry, flow cytometry, and cytokine and chemokine arrays.

NETs promote macrophage phagocytosis both in vitro and in vivo. Neutrophil elastase (NE), which was able to inactivate the canonical signal of protease-activated receptor 2 (PAR2), downregulated the phagocytotic checkpoint CD24. Notably, PAR2 deficiency imitated the effect of NETs on phagocytosis and CD24. Mechanistic studies indicated that inhibiting PAR2 expression upregulated miR-34a and miR-146a and downregulated CD24 in cancer cells. In addition, PAR2 depletion enhanced the recruitment and M1 polarization of macrophages by upregulating CSF-1 and CXCL1. The correlation of NETs/NE and CD24 was corroborated using human CRC specimens. Furthermore, PAR2 blockade combined with an anti-EGFR antibody (cetuximab (CTX)) synergistically enhanced the phagocytic ability of macrophages and suppressed liver metastasis in vivo.

NET-derived elastase inactivated PAR2 canonical signaling and promoted phagocytosis by downregulating CD24, which functions as a phagocytotic checkpoint in CRC liver metastasis. Thus, PAR2 inhibitors combined with CTX may serve as a novel therapeutic strategy against advanced CRC.

Tumor-infiltrating myeloid cells (TIMs), which encompass tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), and tumor-associated dendritic cells (TADCs), are of great importance in tumor microenvironment (TME) and are integral to both pro- and anti-tumor immunity. Nevertheless, the phenotypic heterogeneity and functional plasticity of TIMs have posed challenges in fully understanding their complexity roles within the TME. Emerging evidence suggested that the presence of TIMs is frequently linked to prevention of cancer treatment and improvement of patient outcomes and survival. Given their pivotal function in the TME, TIMs have recently been recognized as critical targets for therapeutic approaches aimed at augmenting immunostimulatory myeloid cell populations while depleting or modifying those that are immunosuppressive. This review will explore the important properties of TIMs related to immunity, angiogenesis, and metastasis. We will also document the latest therapeutic strategies targeting TIMs in preclinical and clinical settings. Our objective is to illustrate the potential of TIMs as immunological targets that may improve the outcomes of existing cancer treatments.

The progression of malignant tumors leads to the development of secondary tumors in various organs, including bones, the brain, liver, and lungs. This metastatic process severely impacts the prognosis of patients, significantly affecting their quality of life and survival rates. Research efforts have consistently focused on the intricate mechanisms underlying this process and the corresponding clinical management strategies. Consequently, a comprehensive understanding of the biological foundations of tumor metastasis, identification of pivotal signaling pathways, and systematic evaluation of existing and emerging therapeutic strategies are paramount to enhancing the overall diagnostic and treatment capabilities for metastatic tumors. However, current research is primarily focused on metastasis within specific cancer types, leaving significant gaps in our understanding of the complex metastatic cascade, organ-specific tropism mechanisms, and the development of targeted treatments. In this study, we examine the sequential processes of tumor metastasis, elucidate the underlying mechanisms driving organ-tropic metastasis, and systematically analyze therapeutic strategies for metastatic tumors, including those tailored to specific organ involvement. Subsequently, we synthesize the most recent advances in emerging therapeutic technologies for tumor metastasis and analyze the challenges and opportunities encountered in clinical research pertaining to bone metastasis. Our objective is to offer insights that can inform future research and clinical practice in this crucial field.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, and its onset and progression are closely associated with epigenetic modifications, particularly post-translational modifications of histones (HPTMs). In recent years, advances in mass spectrometry (MS) have revealed a series of novel HPTMs, including succinylation (Ksuc), citrullination (Kcit), butyrylation (Kbhb), lactylation (Kla), crotonylation (Kcr), and 2-hydroxyisobutyrylation (Khib). These modifications not only expand the histone code but also play significant roles in key carcinogenic processes such as tumor proliferation, metastasis, and metabolic reprogramming in HCC. This review provides the first comprehensive analysis of the impact of novel HPTMs on gene expression, cellular metabolism, immune evasion, and the tumor microenvironment. It specifically focuses on their roles in promoting tumor stem cell characteristics, epithelial-mesenchymal transition (EMT), and therapeutic resistance. Additionally, the review highlights the dynamic regulation of these modifications by specific enzymes, including "writers," "readers," and "erasers."

Neutrophil extracellular traps (NETs) are associated with diseases linked to aberrant coagulation. The blood clotting cascade involves a series of proteases, some of which induce NET formation via a yet unknown mechanism. We hypothesized that this formation involves signaling via a factor Xa (FXa) activation of the protease-activated receptor 2 (PAR2). Our findings revealed that NETs can be triggered in vitro by enzymatically active proteases and PAR2 agonists. Intravital microscopy of the liver vasculature revealed that both FXa infusion and activation of endogenous FX promoted NET formation, effects that were prevented by the FXa inhibitor, apixaban. Unlike classical NETs, these protease-induced NETs lacked bactericidal activity and their proteomic signature indicates their role in inflammatory disorders, including autoimmune diseases and carcinogenesis. Our findings suggest a novel mechanism of NET formation under aseptic conditions, potentially contributing to a self-amplifying clotting and NET formation cycle. This mechanism may underlie the pathogenesis of disseminated intravascular coagulation and other aseptic conditions.

There are currently no relevant studies at home or abroad that combine inflammatory indicators and nomograms to predict the prognosis of gastrointestinal stromal tumor (GIST) patients after surgery. The purpose of this study was to investigate the predictive value of related inflammatory indicators [systemic immune-inflammation index (SII), neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and monocyte/Lymphocyte ratio (MLR)] in patients undergoing GIST surgery, incorporating relevant risk factors to establish a nomogram prediction model, with the aim of better predicting the prognosis of GIST patients.

To explore the relationships between the SII, NLR, PLR, and MLR and postoperative recurrence in patients with GIST.

This study retrospectively included patients who underwent GIST surgery from January 2014 to January 2017 and analyzed the potential relationships between the preoperative SII, NLR, PLR, and MLR and clinicopathological features. The independent risk factors influencing the prognosis of GIST patients were obtained via multivariate regression analysis, and a nomogram model based on the independent risk factors was established.

Among the 124 GIST patients included in the present study, 31 (25%) experienced recurrence within 5 years. Kaplan-Meier survival analysis revealed a correlation between the MLR and PLR and tumor size (P = 0.016 and P = 0.002, respectively). The preoperative SII, MLR, NLR, and PLR were significantly associated with recurrence-free survival (RFS) (P < 0.05). The multivariate analysis results identified the PLR, MLR, and targeted therapy as independent prognostic factors for patient outcomes.

Preoperative MLR and PLR, which are independent risk factors for GIST recurrence, were correlated with RFS. Nomograms based on the PLR, MLR and targeted therapy can be used for clinical treatment.

Neuroblastoma (NB) is a malignant tumor originating from the peripheral sympathetic nervous system and high-risk NB patients have a dismal prognosis. Recent studies have underscored the pivotal role of neutrophil extracellular traps (NETs) in the proliferation, metastasis and immune evasion of cancer. To explore the effect of NETs on NB, we have carried out a systematic analysis and showed several findings in the present work. First, expression profiles along with clinical data were analyzed using the training dataset GSE62564 and 36 NETs-related genes were identified to be significantly associated with overall survival. Following LASSO regression analysis, 11 genes were enrolled to construct the NETs signature, which exhibited a robust predictive capability for overall survival with exhibiting high AUC values within the training set. Validation cohorts confirmed a similar predictive efficacy. Next, NB patients were classified into subgroups based on median risk scores and differentially expressed genes were analyzed. Furthermore, the study performed comprehensive analyses encompassing functional enrichment, immune infiltration and drug sensitivity. Enrichment analysis revealed that the high-risk NBs with high-risk score displayed characteristics of oncogenic malignancy, poor prognosis and immunosuppression. Notably, the risk score exhibited a strong correlation with infiltration levels of various immune cells and the sensitivity to anti-cancer drugs, and was further recognized as an independent prognostic factor for NB patients. In summary, our study elucidates a novel NETs-related gene signature comprising 11 genes, which serves a reliable predictor for NB prognosis.

The combined assessment of the neutrophil-platelet score and prognostic nutritional index is yet to be applied in evaluating the prognosis of patients following an operation for esophageal cancer. This study aimed to identify independent prognostic factors for patients undergoing operation for esophageal cancer and to construct a nomogram model for predicting median overall survival (mOS).

A cohort of 660 patients with esophageal cancer from two clinical centers in China was recruited, comprising a training cohort (n = 511) and a validation cohort (n = 149). Survival rates were compared using Kaplan-Meier curves and the log-rank test. The Cox regression model was used to identify independent prognostic factors.

The Multi-variable Cox regression analysis revealed that tumor, node, metastasis stage, smoking status, neutrophil-platelet score, and prognostic nutritional index were independent postoperative prognostic factors for patients with esophageal cancer (P < 0.05). The mOS (129.0 months, 95% confidence interval (CI) not reached) was significantly higher in patients with a low neutrophil-platelet score than those with a high score (43.0 months, 28.1-57.9; P < 0.05). Conversely, the mOS (42.0 months, 95% CI 6.7-55.2) was lower in the low prognostic nutritional index score group than the high score group (125.0 months, 95% CI 96.4-153.6; P < 0.05). Evaluation metrics, including the concordance index (0.69 in the training group and 0.70 in the validation group), receiver operator characteristic curve analysis (In the training cohort, the AUCs for predicting 1-, 3-, 5- and 10-year overall survival rates using the nomogram were 76.19%, 69.07%, 70.12% and 68.17%, respectively; in the validation cohort, the corresponding predicted values were 76.66%, 77.18%, 75.04% and 79.57%, respectively), calibration curve, and decision curve analysis, demonstrated the clinical utility of the constructed prediction model.

Serving as systemic inflammatory biomarkers, the neutrophil-platelet score and prognostic nutritional index offer valuable prognostic insights for patients with esophageal cancer, augmenting predictive capabilities.

Lung cancer is the leading cause of cancer-related deaths. An enhanced understanding of the immune microenvironments within these tumours may foster more precise and efficient treatment, particularly for immune-targeted therapies. The spatial architectural differences between lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are relatively unexplored. Here, we applied imaging mass cytometry to a balanced cohort of LUAD and LUSC patients, matched for clinical factors such as age, sex, and smoking history, to analyze 204 histopathology images of tumours from 102 individuals with non-small cell lung cancer (NSCLC). By analyzing interactions and broader cellular networks, we interrogate the tumour microenvironment to understand how immune cells are spatially organized in clinically matched adenocarcinoma and squamous cell carcinoma subsets. This spatial analysis revealed distinct patterns of immune cell aggregation, particularly among macrophage populations, that correlated with patient prognosis differentially in adenocarcinoma and squamous cell carcinoma, suggesting potential new strategies for therapeutic intervention. Our findings underscore the importance of analyzing NSCLC histological subtypes separately when investigating the spatial immune landscape, as microenvironmental characteristics and cellular interactions differed by subtype. Recognizing these distinctions is essential for designing precision therapies tailored to each subtype's unique immune architecture, ultimately enhancing patient outcomes.

Previous studies have demonstrated that peptidylarginine deiminase 4 (PAD4) functions as a suppressor, promoter, or both in cancer pathogenesis and therapeutic outcomes. Although PAD4 expression has been proposed to be one of the molecular features of gastric cancer (GC), the biological basis of PAD4 in GC progression and chemotherapy has not been formally established.

Cell type-preferential expression of PAD4 was analyzed in both preclinical and clinical models. The colocalization of PAD4 expression and tumor-infiltrating neutrophils in GC patients was evaluated by immunofluorescence assay. The effects of forced expression of PAD4 on GC cell proliferation were evaluated both in vitro and in vivo. The effects of forced expression of PAD4 on the cytotoxicity of 5-fluorouracil and oxaliplatin were performed by EdU, Annexin V/PI, and comet assays. Co-immunoprecipitation assay was used to investigate the endogenous and exogenous interaction between PAD4 and p53. To investigate whether p53 participated in the chemopotentiating effects of PAD4, small interfering RNA (siRNA)-mediated knockdown of p53 was conducted in PAD4-overexpressing GC cells.

Contrary to the previous report, we initially observed that PAD4 was underexpressed in GC patients and presented as a favorable prognostic factor across the TCGA cohort. Interestingly, the normal gastric epithelial cell line GES-1 exhibited low-level expression of PAD4. In comparison, PAD4 was not detected in GC cell lines, including AGS, HGC-27, and MKN-45. Using an orthotopic mouse model of GC, we found that PAD4 was surprisingly abundant in HGC-27 cell line-derived xenografts. Immunofluorescence staining for PAD4 and neutrophil elastase indicated that PAD4 was mainly expressed in neutrophils but not in GC cells. PAD4 expression was upregulated in all-trans retinoic acid-induced neutrophil-like dHL-60 cells, which were used as a positive control for PAD4 expression. Surprisingly, the enforced expression of PAD4 suppressed the proliferation of GC cells in vitro and in vivo. In addition, cells harboring high PAD4 expression were more susceptible to G1/S boundary arrest, apoptotic death, and DNA damage by regulating p53 target proteins. Mechanistically, PAD4 might affect p53 function through physical interaction with p53, and the chemopotentiating effects of PAD4 could be compromised by p53 knockdown.

PAD4 appeared to be constitutively expressed in tumor-infiltrating neutrophils but not in GC cells. Our findings highlight unique roles of PAD4, in which origin-dependent PAD4 might work complementarily on the progression and treatment vulnerability of GC.

Immune-checkpoint inhibitors (ICIs) have revolutionized melanoma treatment, yet approximately half of patients do not respond to these therapies. Identifying prognostic biomarkers is crucial for treatment decisions. Our retrospective study assessed liquid biopsies and tumor tissue analyses for two potential biomarkers: danger-associated molecular pattern (DAMP) S100A8/A9 and its source, neutrophils. In 43 metastatic unresected stage III/IV melanoma patients, elevated serum levels of S100A8/A9 and neutrophils before and during ICI treatment correlated with worse outcomes. Furthermore, in 113 melanoma patients, neutrophil expression in the tumor microenvironment (TME) was associated with relapse and reduced survival. Measuring S100A8/A9 and neutrophils could enhance immunotherapy monitoring by predicting impaired clinical outcomes and non-response to ICIs. Serum S100A8/A9 levels and neutrophil counts at baseline (T0) and during treatment (T3) correlated with reduced progression-free survival (PFS). Elevated S100A8/A9 levels at T0 and T3 negatively impacted overall survival (OS). Notably, neutrophil infiltration was more prevalent in primary melanomas than in nevi and metastases, and its presence in primary melanomas was linked to poorer survival. S100A8/A9 serum levels, neutrophil counts, and tumor-associated neutrophil infiltration represent promising biomarkers for predicting treatment response and clinical outcomes in melanoma patients receiving ICIs. SIGNIFICANCE: These findings underscore the critical need for reliable biomarkers in melanoma research, particularly for predicting responses to immune-checkpoint inhibitors (ICIs). Identifying S100A8/A9 levels and neutrophil infiltration as potential indicators of treatment outcomes offers valuable insights for personalized therapy decisions. By enhancing monitoring and prognosis assessment, these biomarkers contribute to refining treatment strategies, ultimately improving patient care and outcomes. This research bridges gaps in understanding melanoma response mechanisms and highlights avenues for further investigation into immune-related markers, fostering advancements in precision medicine for melanoma patients.

The present immune therapy was focused on the immune checkpoint blockade or Chimeric Antigen Receptor T-Cell Immunotherapy (CART) transfer, but how to activate the innate immune system to antitumor still lags out. Neutrophils are the most abundant circulating leukocytes in human, and heterogeneous neutrophils have been increasingly recognized as important players in tumor progression. They play double "edge-sward" by either supporting or suppressing the tumor growth, including driving angiogenesis, extracellular matrix remodeling to promote tumor growth, participating in antitumor adaptive immunity, or killing tumor cells directly to inhibit the tumor growth. The complex role of neutrophils in various tumors depends on the tumor microenvironment (TME) they are located, and emerging evidence has suggested that neutrophils may determine the success of tumor immunotherapy in the context of the immune checkpoint blockade, innate immune training, or drug-loaded extracellular microvesicles therapy, which makes them become an exciting target for tumor immunotherapy, but still with challenges. Here, we summarize the latest insights on how to activate neutrophils in antitumor immunity and discuss the advances of neutrophil-targeted immunotherapy strategies.

This study aims to create and validate a novel systematic immune-inflammation-nutrition (SIIN) score to provide a non-invasive and accurate prognostic tool for head and neck squamous cell carcinoma (HNSCC) patients.

259 participants diagnosed with HNSCC from the First Affiliated Hospital of Xi'an Jiaotong University between 2008 and 2017 was included in this retrospective study. Patients were assigned to training (n=181) and validation (n=78) sets. A LASSO Cox regression model was employed to identify significant biomarkers for constructing a SIIN nomogram and to create SIIN score from this nomogram. The prognostic accuracy of the SIIN score was assessed by exploiting receiver operating characteristic (ROC) analysis, Kaplan-Meier survival analysis, Cox proportional hazard regression models, calibration and DCA curves.

The SIIN score was formulated based on six biomarkers-platelet-lymphocyte ratio (PLR), prognostic nutritional index (PNI), systemic immune-inflammation index (SII), albumin-bilirubin index (ALBI), fibrinogen (FIB) and monocyte count-identified by LASSO regression analysis. (1)The SIIN score demonstrated superior predictive value, achieving area under the ROC curve (AUC) values of 0.736 and 0.700 for 3- and 5-year OS. For recurrence-free survival (RFS), the AUC values were 0.752 for 3-year and 0.701 5-year RFS, as assessed in the training set. Validated as an independent prognostic factor in both cohorts, the SIIN score showed strong correlation with adverse clinicopathological outcomes.

The SIIN score is a promising prognostic tool that integrates immune, inflammatory, and nutritional factors for predicting clinical outcomes in HNSCC patients. It offers enhanced predictive accuracy compared to existing markers and has the potential to guide personalized treatment strategies and clinical decision-making.

There is a renewed interest in neutrophil biology, largely instigated by their prominence in cancer. From an immunologist's perspective, a conceptual breakthrough is the realization that prototypical inflammatory, cytotoxic leukocytes can be tamed to promote the survival and growth of other cells. This has sparked interest in defining the biological principles and molecular mechanisms driving the adaptation of neutrophils to cancer. Yet, many questions remain: is this adaptation mediated by reprogramming mature neutrophils inside the tumoral mass, or rather by rewiring granulopoiesis in the bone marrow? Why, in some instances, are neutrophils beneficial and in others detrimental to cancer? How many different functional programs can be induced in neutrophils by tumors, and is this dependent on the type of tumor? This review summarizes what we know about these questions and discusses therapeutic strategies based on our incipient knowledge of how neutrophils adapt to cancer.

Disseminated cancer cells in the peritoneal fluid often colonize omental fat-associated lymphoid clusters but the mechanisms are unclear. Here, we identify that innate-like B cells accumulate in the omentum of mice and women with early-stage ovarian cancer concomitantly with the extrusion of chromatin fibers by neutrophils called neutrophil extracellular traps (NETs). Studies using genetically modified NET-deficient mice, pharmacologic inhibition of NETs, and adoptive B cell transfer show that NETs induce expression of the chemoattractant CXCL13 in the pre-metastatic omentum, stimulating recruitment of peritoneal innate-like B cells that in turn promote expansion of regulatory T cells and omental metastasis through producing interleukin (IL)-10. Ex vivo studies show that NETs elicit IL-10 production in innate-like B cells by inactivating SHP-1, a phosphatase that inhibits B cell activation pathways, and by generating reactive oxygen species. These findings reveal that NETs alter immune cell dynamics in the pre-metastatic omentum, rendering this niche conducive for colonization.

Myeloid cells accumulate extensively in most tumors and play a critical role in immunosuppression of the tumor microenvironment (TME). Like T cells, myeloid cells also express immune checkpoint molecules, which induce the immunosuppressive phenotype of these cells. In this review, we summarize the tumor-promoting function and immune checkpoint expression of four types of myeloid cells: macrophages, neutrophils, dendritic cells, and myeloid-derived suppressor cells, which are the main components of the TME. By summarizing the research status of myeloid checkpoints, we propose that blocking immune checkpoints on myeloid cells might be an effective strategy to reverse the immunosuppressive status of the TME. Moreover, combining nanotechnology, cellular therapy, and bispecific antibodies to achieve precise targeting of myeloid immune checkpoints can help to avoid the adverse effects of systemic administration, ultimately achieving a balance between efficacy and safety in cancer therapy.

This chapter reviews tumor-associated myeloid cells, including macrophages, neutrophils, and other innate immune cells, and their multifaceted roles in supporting breast cancer progression and metastasis. In primary tumors, myeloid cells play key roles in promoting tumor epithelial-mesenchymal transition (EMT) and invasion. They can facilitate intravasation (entry into the bloodstream) and colonization, disrupting the endothelial cell layer and reshaping the extracellular matrix. They can also stimulate angiogenesis, suppress immune cell responses, and enhance cancer cell adaptability. In the bloodstream, circulating myeloid cells enable the survival of disseminated tumor cells via immunosuppressive effects and physical shielding. At the metastatic sites, they prime the premetastatic niche, facilitate tumor cell extravasation, and support successful colonization and outgrowth. Mechanistically, myeloid cells enhance cancer cell survival, dormancy escape, proliferation, and mesenchymal-epithelial transition (MET). Nonetheless, substantial gaps in our understanding persist regarding the functional and spatiotemporal diversity, as well as the evolutionary patterns, of myeloid cells during metastatic progression. Myeloid cell plasticity and differential responses to therapies present key barriers to successful treatments. Identifying specific pro-tumoral myeloid cell subpopulations and disrupting their interactions with cancer cells represent promising therapeutic opportunities. Emerging evidence suggests combining immunomodulators or stromal normalizers with conventional therapies could help overcome therapy-induced immunosuppression and improve patient outcomes. Overall, further elucidating myeloid cell heterogeneity and function throughout the process of breast cancer progression and metastasis will enable more effective therapeutic targeting of these critical stromal cells.

Colorectal cancer encompasses a heterogeneous group of malignancies that differ in pathophysiological mechanisms, immune response and infiltration, therapeutic response, and clinical prognosis. Numerous studies have highlighted the clinical relevance of tumor-infiltrating immune cells among different types of colorectal tumors yet vary in cell type definitions and cell identification strategies. The distinction of immune signatures is particularly challenging when several immune subtypes are involved but crucial to identify novel intercellular mechanisms within the tumor microenvironment. In this review, we compile human and non-human studies on tumor-infiltrating immune cells and provide an overview of immune subtypes, their pathophysiological functions, and their prognostic role in colorectal cancer. We discuss how differentiating immune signatures can guide the development of immunotherapeutic targets and personalized treatment regimens. We analyzed comprehensive human protein biomarker profiles across the entire immune spectrum to improve interpretability and application of tumor studies and to ultimately enhance immunotherapy and advance precision medicine for colorectal cancer patients.

Variations in light exposure are associated with changes in inflammation and coagulation. The impact of light spectra on venous thrombosis (VT) and arterial thrombosis is largely unexplored.

To investigate the impact of altering light spectrum on platelet function in thrombosis.

Wild-type C57BL/6J mice were exposed to ambient (micewhite, 400 lux), blue (miceblue, 442 nm, 1400 lux), or red light (micered, 617 nm, 1400 lux) with 12:12 hour light:dark cycle for 72 hours. After 72 hours of light exposure, platelet aggregation, activation, transcriptomic, and metabolomic changes were measured. The ability of released products of platelet activation to induce thrombosis-generating neutrophil extracellular trap formation was quantified. Subsequent thrombosis was measured using murine models of VT and stroke. To translate our findings to human patients, light-filtering cataract patients were evaluated over an 8-year period for rate of venous thromboembolism with multivariable logistic regression clustered by hospital.

Exposure to long-wavelength red light resulted in reduced platelet aggregation and activation. RNA-seq analysis demonstrated no significant transcriptomic changes between micered and micewhite. However, there were global metabolomic changes in platelets from micered compared with micewhite. Releasate from activated platelets resulted in reduced neutrophil extracellular trap formation. Micered also had reduced VT weight and brain infarct size following stroke. On subgroup analysis of cataract patients, patients with a history of cancer had a lower lifetime risk of venous thromboembolism after implantation with lenses that filter low-wavelength light.

Light therapy may be a promising approach to thrombus prophylaxis by specifically targeting the intersection between innate immune function and coagulation.

Lung adenocarcinoma (LUAD) is associated with high morbidity and mortality rates. Increasing evidence indicates that neutrophil extracellular traps (NETs) play a critical role in tumor progression, metastasis and immunosuppression in the LUAD tumor microenvironment (TME). Nevertheless, the use of NET formation-related genes (NFRGs) to predict LUAD patient survival and response to immunotherapy has not been explored. Therefore, this study aimed to construct a NFRGs-based prognostic signature for stratifying LUAD patients and informing individualized management strategies.

The cell composition of the LUAD TME was investigated using the single-cell sequencing data in Single-Cell Lung Cancer Atlas (LuCA). NFRGs were identified to construct a prognostic signature based on The Cancer Genome Atlas (TCGA) cohort which was validated in the Gene Expression Omnibus (GEO) dataset. The univariate Cox and least absolute shrinkage and selection operator (LASSO) Cox regression models, receiver operating characteristic (ROC) and Brier Score were applied to assess the prognostic model. A nomogram was established to facilitate the clinical application of the risk score. The Estimation of STromal and Immune cells in MAlignant Tumor tissues (ESTIMATE) and Tumor Immune Dysfunction and Exclusion (TIDE) algorithm were utilized to assess the TME and predict immunotherapy response. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was applied to quantify the expression levels of four NFRGs in LUAD paired tissue samples.

Single‑cell RNA sequence analysis showed the importance of neutrophils in LUAD TME. We developed and validated a 4-NFRG (CAT, CTSG, ENO1, TLR2) prognostic signature based on TCGA and GEO cohorts, which stratified patients into high-risk and low-risk groups. Univariate and multivariate analyses showed that our risk model could independently predict the survival of LUAD patients. Patients in the low-risk group exhibited a more active immune microenvironment, lower TIDE scores, lower half-maximal inhibitory concentration (IC50) values and higher immune checkpoint molecule expression. Our risk signature could serve as a biomarker for predicting immunotherapeutic benefits.

We developed a novel prognostic signature for LUAD patients based on NFRGs and emphasized the critical role of this signature in predicting LUAD patient survival and immunotherapy response.

Neutrophil extracellular traps (NETs) have been shown to exhibit chemotactic effects on circulating tumor cells at metastatic sites, promoting the progression of colorectal cancer liver metastasis (CRLM). However, the origin and factors contributing to the formation of NETs (NETosis) in the pre-metastatic niche (PMN) of target organs remain unclear. In this study, we investigated the relationship between phosphatase of regenerating liver-3 (PRL-3), myeloid-derived suppressor cells (MDSCs), neutrophils, and NETs through a retrospective clinical cohort study and a mouse model of CRLM. Our clinical findings revealed associations between PRL-3 expression and the infiltration of neutrophils and MDSCs in CRLM patients. Moreover, NETosis emerged as a robust indicator of poor prognosis for overall survival in these patients. In CRLM models, PRL-3 overexpression enhanced both primary tumor growth and liver metastasis. We found that the first week after tumor cell implantation appeared to be a crucial period for PMN formation, with notable infiltration of neutrophils, MDSCs, and NETosis during this time. Notably, co-culturing neutrophils with MDSCs induced NETosis in vitro, particularly with granulocyte-like MDSCs (Gr-MDSCs), the predominant subtype of infiltrating MDSCs. In summary, our findings elucidate the likely origin of NETs in the PMN during CRLM development and underscore the significant influence of PRL-3. These findings may offer potential immunotherapeutic targets for patients at risk of developing CRLM, warranting further investigation in clinical settings.

Although surgical resection of tumor mass remains the mainstay of curative therapeutic management for solid tumors, accumulating studies suggest that these procedures promote tumor recurrence and metastasis. Regarded as the first immune cells to fight against infectious or inflammatory insults from surgery, neutrophils along with their ability of neutrophil extracellular traps (NETs) production has attracted much attention. A growing body of evidence suggests that NETs promote cancer metastasis by stimulating various stages, including local invasion, colonization, and growth. Therefore, we discussed the mechanism of NETosis induced by surgical stress and tumor cells, and the contribution of NETs on tumor metastasis: aid in the tumor cell migration and proliferation, evasion of immune surveillance, circulating tumor cell adhesion and establishment of a metastatic niche. Lastly, we summarized existing NET-targeting interventions, offering recent insights into potential targets for clinical intervention.

Animal genomes are packaged into chromatin, a highly dynamic macromolecular structure of DNA and histone proteins organised into nucleosomes. This accommodates packaging of lengthy genomic sequences within the physical confines of the nucleus while also enabling precise regulation of access to genetic information. However, histones existed before chromatin and have lesser-known functions beyond genome regulation. Most notably, histones are potent antimicrobial agents, and the release of chromatin to the extracellular space is a defence mechanism nearly as ancient and widespread as chromatin itself. Histone sequences have changed very little throughout evolution, suggesting the possibility that some of their 'non-canonical' functions are at play in parallel or in concert with their genome regulatory functions. In this Review, we take an evolutionary perspective of histone, nuclear chromatin and extracellular chromatin biology and describe the known extranuclear and extracellular functions of histones. We detail molecular mechanisms of chromatin release and extracellular chromatin sensing, and we discuss their roles in physiology and disease. Finally, we present evidence and give a perspective on the potential of extracellular histones to act as bioactive, cell modulatory factors.

Active neutrophils play a variety of roles in both innate and adaptive immune responses, and one of the most vital roles is the formation and release of neutrophil extracellular traps (NETs). NETs are created when neutrophils release their chromatin contents to get and eradicate pathogenic organisms essentially. While NET helps fight bacteria, viruses, parasites, and infections, it is also linked to asthma, atherosclerosis, and cancer metastasis. Thus, understanding the molecular mechanisms behind NETosis formation and its inhibition is crucial for developing safe and effective therapies. This systematic review aims to identify the list of miRNAs that are associated with the formation of NETosis and illustrate the mechanism of action by classifying them based on their expression site. Moreover, it summarizes the list of miRNAs that can be targeted therapeutically to reduce NETosis in various disorders. The current study entailed the searching of PubMed and Google Scholar for articles related to the research topic role of miRNAs in NETosis in all types of disorders. The search terms and phrases included "NETs," "neutrophil extracellular traps," "NETosis," "miRNA," "miR," and "micro-RNA." The search was limited to articles published in English since October 2024 in both databases. Following a review of 23 papers, 19 of them met the inclusion and exclusion criteria of this study. Four papers have been removed as they are duplicated or do not meet our criteria. According to the published articles till October 2024, there are 14 miRNAs involved in the molecular pathway of NETosis which are miR-155, miR-1696, miR-7, miR-223, miR-146a, miR-142a-3p, miR-3146, miR-505, miR-4512, miR-15b-5p, miR-16-5p, miR-26b-5p, miR-125a-3p and miR-378a-3p. Moreover, eight miRNAs have been identified as possible therapeutic targets for the suppression of NETosis based on in-vivo studies carried out in various organisms, which are miR-155, miR-146a, miR-1696, miR-223, miR-142a-3p, miR-3146, miR-4512, miR-16-5p. Different miRNAs that are expressed inside or outside of neutrophils can regulate and influence NETosis. Eight miRNAs have also been identified as potential therapeutic targets, which can be utilized to inhibit the molecular pathways associated with NETosis and prevent its negative effects, such as asthma, atherosclerosis, cancer metastasis, and cancer recurrence. However, further human-based research is necessary to completely understand the role of miRNAs in the development of NETosis in humans.

The complexity and heterogeneity of neutrophils are recognized, especially their roles in modulating inflammation and cancer immune responses. The detailed functions of neutrophils in human tumour-draining lymph nodes (TDLNs), specifically in the context of head and neck cancer, remain inadequately characterized.

This study aims to delineate the phenotypic diversity of neutrophils in TDLNs, non-tumour-draining lymph nodes (nTDLNs) from patients with oral squamous cell carcinoma (OSCC), and to evaluate their correlation with clinical outcomes.

A flow cytometry-based investigation.

Neutrophils manifest a tissue-specific heterogeneity with significant phenotypic differences between compartments. A substantial fraction of neutrophils displayed an activated CD16highCD62Ldim profile in TDLNs, more prominent in patients with advanced T stages, implicating their involvement in the disease's progression. Notably, the presence of this activated neutrophil phenotype in TDLNs was strongly associated with poorer patient prognosis.

The study confirms the heterogeneity of neutrophils in human TDLNs, aligning with findings from animal models but extending them to show clinical relevance in human disease. The correlation of neutrophil phenotypes with cancer progression and prognosis emphasizes the importance of these cells in the tumour-microenvironment. The data suggests a future possibility to develop targeted therapies that modulate the neutrophilic response in OSCC.

Ovarian cancer (OvCa) is the most lethal gynaecology malignancies worldwide. Neutrophil extracellular traps (NETs), net-like protein structures produced by activated neutrophils and DNA-histone complexes, have a central role in tumours, though haven't been fully explored in OvCa. We obtained transcriptome data from TCGA-OvCa database (n = 376) as training, ICGC-OvCa database (n = 111) as validation and GTEx database (n = 180) as controls. Through LASSO-COX Regression analysis, we identified an eight-gene signature among 87 NETs-related genes, which was significantly related to poor prognosis in both TCGA-OvCa and ICGC-OvCa cohorts (Log-rank p-value = 0.0003 and 0.0014). Next, we constructed and validated a prognostic nomogram, consist of NETs-related signature and clinical features (C-index = 0.82). We evaluated 22 typical immune cell infiltration through CIBERSORT analysis, which implied upregulation of memory CD4 + T cells, follicular helper T cells and neutrophils in high-risk group. Additionally, we predicted therapy sensitivity through TIDE algorithm, indicating that high NETs-riskscore exhibited more sensitivity towards Sorafenib and less sensitivity towards immunotherapy. We initially reported that RAC2 upregulation was associated with NETs formation and poor prognosis (p-value < 0.05) through IHC analysis of tissue microarrays (n = 125). Conclusively, NETs-related signature was reliable for OvCa prognosis prediction and therapy assessment. Especially, RAC2 was predominantly related to NETs formation, thus providing hints towards anti-tumour mechanism of NETs in OvCa.

Bone marrow is pivotal for normal hematopoiesis and immune responses, yet it is often compromised by malignancies. The bone microenvironment (BME), composed of bone and immune cells, maintains skeletal integrity and blood production. The emergence of primary or metastatic tumors in the skeletal system results in severe complications and contributes significantly to cancer-related mortality. These tumors set off a series of interactions among cancer, bone, and immune cells, and disrupt the BME locally or distantly. However, the drivers, participants, and underlying molecules of these interactions are not fully understood. This review explores the crosstalk between bone metabolism and immune responses, synthesizing current knowledge on the intersection of cancer and osteoimmune biology. It outlines how bone marrow immune cells can either facilitate or hinder tumor progression by interacting with bone cells and pinpoints the molecules responsible for immunosuppression within bone tumors. Moreover, it discusses how primary tumors remotely alter the BME, leading to systemic immune suppression in cancer patients. This knowledge provides critical rationales for emerging immunotherapies in the treatment of bone-related tumors. Taken together, by summarizing the intricate relationship between tumor cells and the BME, this review aims to deepen the understanding of the diversity, complexity, and dynamics at play during bone tumor progression. Ultimately, it highlights the potential of targeting bone-tumor interactions to correct aberrant immune functions, thereby inhibiting tumor growth and metastasis.

BackgroundDistant metastasis (DM) remains the most commonly reported cause of death in patients with urothelial carcinoma of the bladder (UCB).ObjectiveWe aimed to develop a robust prognostic model to assess the risk of DM in patients with UCB.MethodsWe collected clinical data of 206 UCB patients treated with RC. Patients treated with RC between 2011-2015 that were enrolled as the training cohort (n = 105), while the patients between 2016-2019 were enrolled as the validation cohort (n = 101). Univariate and multivariate Cox regression models were used to identify independent risk factors associated with DM. We identified the variables by stepwise regression and established nomogram. We evaluated the nomograms using C-index, calibration and ROC curves. Decision curve analysis was performed to compare the net benefits between the nomogram and TNM staging. We divided the patients into high and low risk groups according to the nomogram and compared the DM between the groups.ResultsThe neutrophil-lymphocyte ratio (NLR) was an independent predictor of DM. We established nomogram by T-stage, N-stage and NLR. The C-index of the nomogram was 0.766 and 0.739 respectively in the two cohorts. In the training cohort, AUC for the nomogram at 1, 2 and 3 years was 0.816, 0.812 and 0.812, respectively. In the validation cohort, the AUC for the nomogram at 1, 2 and 3 years was 0.751, 0.757 and 0.716, respectively. The calibration curve was satisfactory. The nomogram has a higher clinical benefit compared to the TNM staging system. Kaplan-Meier curves showed that patients from the high-risk group had a higher probability of DM than patients from the low-risk group.ConclusionsNomograms established by NLR, T-stage and N-stage can accurately predict distant metastases in patients with UCB.