High Helicobacter pylori infection rates contribute to high gastric cancer (GC) incidence. While H. pylori infection is associated with GC development its mechanisms are still being studied. The aim of the present study was to examine the differences between H. pylori infection‑induced GC and non‑infected tissues, and to investigate the correlation between nucleotide‑binding oligomerization domain, leucine rich repeat and pyrin domain containing 3 (NLRP3) inflammasome expression and immune cell infiltration in GC, thus providing a theoretical basis for clinical prognosis and immunotherapy. High‑throughput RNA‑sequencing expression data from The Cancer Genome Atlas (TCGA) were analyzed. Additionally, TIMER2.0 and Kaplan‑Meier Plotter were used to analyze the differential expression of NLRP3 mRNA in various tumors, the effect of H. pylori infection on gene expression, and the association between NLRP3 and clinical prognosis among patients with GC. Immunohistochemistry (IHC) was used to assess the effects of NLRP3 protein expression on immune cell infiltration in clinical tissues with or without H. pylori infection. R software was used for data visualization and statistical analysis. TCGA data revealed that the expression levels of NLRP3 in GC tissues were increased compared with those in normal tissues (P<0.05), which was further validated in clinical samples. Furthermore, NLRP3 mRNA expression was significantly elevated in clinical GC tissues infected with H. pylori. Notably higher relative levels of NLRP3 mRNA were observed in tumor tissues with a tumor size ≥5 cm, lymph node metastasis, Tumor‑Node‑Metastasis stage III + IV or poor differentiation compared with the respective controls (P<0.05). IHC confirmed a significant increase in NLRP3 expression within H. pylori‑infected GC tissues compared with that in non‑infected tissues. In GC immune infiltration, NLRP3 expression was revealed to be associated with natural killer cell, whereas it was negatively correlated with regulatory T cells and CD8+ T cells. These findings indicated that NLRP3 may promote the polarization of tumor‑associated macrophages towards the M2 phenotype. High NLRP3 expression also promoted the infiltration of CD3+ and CD206+ cells, which significantly affected the survival rate of patients with GC. The immune infiltration of regulatory T lymphocytes was associated with better survival benefits for patients with GC; however, M2 macrophage infiltration was not conducive to the survival of patients with GC. Furthermore, survival analysis showed that high expression of NLRP3 was associated with a poorer 5‑year overall survival, progression‑free survival and post‑progression survival rates. In conclusion, elevated NLRP3 expression, which may be induced by H. pylori infection, could promote immune cell infiltration potentially by regulating cancer cell proliferation and migration, ultimately leading to an unfavorable prognosis and a notable reduction in the 5‑year survival rate.

The tumor microenvironment (TME) and aberrant glycosylation have been suggested to play key roles in cancer. This study integrated differentially expressed genes (DEGs) and weighted gene coexpression network analysis (WGCNA) to identify tumor microenvironment-related genes and construct a TME-risk prognostic signature (TMERS) through LASSO Cox regression. After batch effect removal, 44 TME-prognosis-related genes (TMEPGs) were identified and classified into three molecular subtypes via K-means clustering. The finalized 22-gene TMERS model demonstrated robust prognostic predictive capacity in GEO datasets. The results revealed distinct immune profiles and prognostic stratifications among genetic subtypes and risk groups, confirming that the TMERS is an independent prognostic indicator for breast cancer (BRCA). Glycosyltransferase genes (GTs) have potential therapeutic relevance through immune regulation, with TMEPG member killer cell lectin like receptor B1 (KLRB1) significantly correlated with BRCA prognosis. Cellular experiments demonstrated that KLRB1 overexpression suppressed BRCA cell proliferation and migration. This work establishes a novel prognostic model for BRCA while highlighting KLRB1 as a potential biomarker, providing new insights into TME-targeted therapeutic strategies.

Although the systemic inflammation response index (SIRI) is often associated with prognostic significance in esophageal cancer (EC) patients, the results continue to be conflicting. We focused on identifying SIRI's precise role in forecasting EC prognosis through performing this meta-analysis.

This work searched PubMed, Web of Science, Embase, Cochrane Library, and CNKI till November 16, 2024, and determined pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for evaluating EC prognosis forecasting efficiency of SIRI. The inclusion criteria: (1) pathologic confirmation of EC; (2) those reporting associations of SIRI with EC survival outcomes; (3) those reporting HRs and 95% CIs; (4) those with an available cut-off value of SIRI; and (5) no restriction in language. The exclusion criteria: (1) case reports, reviews, meeting abstracts, comments and letters; (2) those enrolling duplicate cases; and (3) animal studies.

We enrolled six studies comprising 2176 cases into the present work. Based on our combined findings, elevated SIRI showed significant relation to dismal overall survival (OS) (HR = 1.43, 95%CI = 1.20-1.71, p < 0.001; I2 = 48.8%, p = 0.098) and shortened progression-free survival (PFS) (HR = 2.00, 95%CI = 1.35-2.98, p = 0.001; I2 = 0, p = 0.409) in EC. Moreover, high SIRI exhibited obvious relation to male gender (OR = 1.86, 95%CI = 1.07-3.22, p = 0.027; I2 = 69.4%, p = 0.020), TNM stage of III-IV (OR = 1.52, 95%CI = 1.18-1.94, p = 0.001; I2 = 24.3%, p = 0.265), T3-T4 stage (OR = 1.73, 95%CI = 1.12-2.69, p = 0.014; I2 = 61.0%, p = 0.053), and lymph node metastasis (OR = 1.29, 95%CI = 1.02-1.64, p = 0.036; I2 = 42.7%, p = 0.155). However, SIRI was not markedly related to age, tumor location, tumor differentiation, or smoking history.

In summary, high SIRI is significantly related to dismal OS and shortened PFS of EC cases, together with advanced tumor stage, T3-T4 stage, and lymph node metastasis of EC. Due to some limitations, large prospective studies that utilize standardized threshold SIRI should be conducted to validate our results in the future.

Recent advancements in technology have significantly expanded the scope of tumor research, progressing from the study of individual cells to more intricate tissue and organ-level analyses. Tumor organoids have emerged as a highly realistic platform for investigating tumor growth, development, and their interactions with the surrounding microenvironment. However, a notable limitation of these organoids is their lack of the diverse cellular composition typically observed in actual tumors, which hinders their ability to fully replicate the complexity of the tumor microenvironment. Immune cells play a pivotal role, and tumor immunology has become a major research hotspot. Research in tumor immunology aims to elucidate how the immune system recognizes and attacks tumor cells, as well as how tumor cells evade immune surveillance. In recent years, there has been growing interest in co-culturing immune cells with tumor organoids, an approach that has yielded valuable insights into the intricate interactions between tumors and the immune system. The aim of this paper is to review and discuss the progress achieved in co-culturing tumor organoids with immune cells. By doing so, we hope to offer a new perspective and enhance our understanding of the complexity and diversity inherent in the tumor microenvironment.

Cancer, an important global health problem, is defined by aberrant cell proliferation and continues to be the main cause of death globally. The tumor microenvironment (TME) plays an essential role in the development of cancer, resistance to therapy, and regulation of the immune response. Some immune cells in the TME, like T cells, B cells, macrophages, dendritic cells, and natural killer cells, can either stop or help tumor growth, depending on how metabolic and cytokine changes happen. Cytokines function as essential signaling molecules that modulate immune cell metabolism, altering their functionality. This review focuses on how cytokine-mediated metabolic reprogramming affects the activity of immune cells inside the TME, which can either make the immune response stronger or weaker. New ways of treating cancer that focus on metabolic pathways and cytokine signaling, such as using IL (Interleukin) - 15, IL- 10, and IL- 4, show promise in boosting immune cell activity and making cancer treatments more effective. Finding these pathways could lead to new ways to treat cancer with immunotherapy that focus on metabolic competition and immune resistance in the TME.

As one of the leading components in the immune system, neutrophils in the tumor microenvironment (TME) have received considerable attention in recent years. The tumor-killing effects of neutrophils in a variety of tumors have been reported. However, the functions of neutrophils in tumors remain to be completely elucidated, and both anti-tumor and tumor-promotion activities have been reported. This review focuses on the characteristics of neutrophils and their mechanisms of action in the TME, with an emphasis on their anti-tumor activity, including reactive oxygen species (ROS)-induced tumor killing, cytotoxic T lymphocytes (CTLs)-induced tumor killing, trogocytosis, cytotoxic enzymes, and trained immunity. Furthermore, the possible targets and methods of tumor treatment regimens for neutrophils are explored, with the aim of exploring the use of neutrophils in the future as a potential anti-tumor treatment strategy.

Neutrophils, the most abundant white blood cells, play a dual role in cancer progression. While they can promote tumor growth, metastasis, and immune suppression, they also exhibit anti-tumorigenic properties by attacking cancer cells and enhancing immune responses. This review explores the complex interplay between neutrophils and the tumor microenvironment (TME), highlighting their ability to switch between pro- and anti-tumor phenotypes based on external stimuli. Pro-tumorigenic neutrophils facilitate tumor growth through mechanisms such as neutrophil extracellular traps (NETs), secretion of pro-inflammatory cytokines, and immune evasion strategies. They contribute to angiogenesis, tumor invasion, and metastasis by releasing vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). Conversely, anti-tumor neutrophils enhance cytotoxicity by generating reactive oxygen species (ROS), promoting antibody-dependent cell-mediated cytotoxicity (ADCC), and activating other immune cells such as cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Recent advances in neutrophil-based drug delivery systems have harnessed their tumor-homing capabilities to improve targeted therapy. Neutrophil-mimicking nanoparticles and membrane-coated drug carriers offer enhanced drug accumulation in tumors, reduced systemic toxicity, and improved therapeutic outcomes. Additionally, strategies to modulate neutrophil activity, such as inhibiting their immunosuppressive functions or reprogramming them towards an anti-tumor phenotype, are emerging as promising approaches in cancer immunotherapy. Understanding neutrophil plasticity and their interactions with the TME provides new avenues for therapeutic interventions. Targeting neutrophil-mediated mechanisms could enhance existing cancer treatments and lead to the development of novel immunotherapies, ultimately improving patient survival and clinical outcomes.

Advanced hepatocellular carcinoma (HCC) presents a strongly immunosuppressive tumor microenvironment, which enables tumor cells to evade immune cell attacks and hinder effective drug killing, thereby hindering the achievement of the desired therapeutic effect. In response, a novel nanoplatform- AuHNR@γ-Fe2O3@Lenvatinib@β-Glucan (AFLG) with surface modified β-1,3-glucan is developed, which exhibits potent immunostimulatory effect and the capability of repolarizing macrophages, to counteract the immunosuppressive conditions present in the tumor microenvironment. Leveraging the hollow structure of gold nanorods, Lenvatinib is efficiently loaded, a first-line targeted drug for HCC, which effectively inhibits tumor angiogenesis. Additionally, through atomic layer deposition, γ-Fe2O3 is generated on the hollow gold nanorod surface, endowing it with chemodynamic therapy and magnetic resonance T2-weighted imaging capabilities while excellently maintaining the gold nanorod's superior photothermal therapy and photoacoustic imaging properties under 1064 nm excitation. These AFLG NPs feature dual-modal imaging and quadruple-modal synergistic therapy capabilities, along with their powerful potential in remodeling the immunosuppressive tumor microenvironment, offering an encouraging novel approach for the treatment of hepatocellular carcinoma.

The complex composition and dynamic change of the tumor microenvironment (TME), mainly consisting of tumor cells, immune cells, stromal cells, and extracellular components, significantly impede the effector function of cytotoxic T lymphocytes (CTL), thus representing a major obstacle for tumor immunotherapies. In this review, we summarize and discuss the impacts and underlying mechanisms of major elements in the TME (different cell types, extracellular matrix, nutrients and metabolites, etc.) on the infiltration, survival, and effector functions of T cells, mainly CD8+ CTLs. Moreover, we also highlight recent advances that may potentiate endogenous antitumor immunity and improve the efficacy of T cell-based immunotherapies in patients with cancer by manipulating components inside/outside of the TME. A deeper understanding of the effects and action mechanisms of TME components on the tumor-eradicating ability of CTLs may pave the way for discovering new targets to augment endogenous antitumor immunity and for designing combinational therapeutic regimens to enhance the efficacy of tumor immunotherapies in the clinic.

Inflammation, a hallmark of cancer, has been associated with tumor progression, transition into malignant phenotype and efficacy of anticancer treatments in cancer. It affects all stages of cancer, from the initiation of carcinogenesis to metastasis. Chronic inflammation induces immunosup-pression, providing an environment conducive to carcinogenesis, whereas acute inflammation induces an antitumor immune response, leading to tumor suppression. Solid tumors have an inflammatory tumor microenvironment (TME) containing cancer cells, immune cells, stromal cells, and soluble molecules, which plays a key role in tumor progression and therapy response. Both cancer cells and stromal cells in the TME are highly plastic and constantly change their phenotypic and functional properties. Cancer-associated inflammation, the majority of which consists of innate immune cells, plays an important role in cancer cell plasticity, cancer progression and the development of anticancer drug resistance. Today, with the combined used of advanced technologies, such as single-cell RNA sequencing and spatial molecular imaging analysis, the pathways linking chronic inflammation to cancer have been largely elucidated. In this review article, we highlighted the molecular and cellular mechanisms involved in cancer-associated inflammation and its effects on cancer progression and treatment response. We also comprehensively review the mechanisms linking chronic inflammation to cancer in the setting of GI cancers.

The standard treatment for breast cancer typically includes surgery, often followed by systemic therapy and individualized treatment regimens. However, there is growing interest in identifying pre-therapeutic biomarkers that can predict tumor response to neoadjuvant chemotherapy (NACT). This study systematically evaluated various analytical parameters, including age, TNM stage, histological type, molecular subtype, and several biomarker ratios, such as the platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammatory index (SII), and prognostic nutritional index (PNI). We aimed to assess the predictive value of these parameters regarding the tumor's response rate to NACT. The analysis revealed a statistically significant association between the pathological complete response-pCR (absence of any detectable cancer cells in the tissue following neoadjuvant chemotherapy (NACT))-rate and NLR in the subgroup with values between 1 and 3 (p = 0.001). The optimal cut-off for PLR was determined to be 120.45, with 80.55% of patients achieving pCR showing PLR values below this threshold (p = 0.000). Similarly, the LMR cut-off was found to be 12.34, with 77.77% of patients with pCR having LMR values below this threshold (p = 0.002). Additionally, lower pre-therapeutic values of NLR (p < 0.001), PLR (p = 0.002), SII (p = 0.001), and LMR (p = 0.001) were significantly correlated with pCR compared to the non-pCR subgroup (p < 0.005). These findings highlight the predictive potential of these biomarkers for achieving pCR following NACT. Our study supports the hypothesis that pre-therapeutic values of NLR, PLR, SII, and LMR can serve as predictive biomarkers for pCR in breast cancer patients undergoing NACT. However, the PNI did not demonstrate predictive potential in relation to pCR. These biomarkers may provide valuable insights into patient prognosis and guide personalized treatment strategies.

The tumor microenvironment is a dynamic and complex three-dimensional network comprising the extracellular matrix and diverse non-cancerous cells, including fibroblasts, adipocytes, endothelial cells and various immune cells (lymphocytes T and B, NK cells, dendritic cells, monocytes/macrophages, myeloid-derived suppressor cells, and innate lymphoid cells). A constantly and rapidly growing number of studies highlight the critical role of these cells in shaping cancer survival, metastatic potential and therapy resistance. This review provides a synthesis of current knowledge on the modulating role of the cellular microenvironment in cancer progression and response to treatment.

Fc receptor γ subunit (FcRγ) activation plays a crucial role in cancer carcinogenesis. Here, we aimed to uncover the impact of FcRγ on circulating tumor cells (CTC) colonization and the underlying mechanism. FcRγ deficient (FcRγ-/-) mice were used to investigate the functional effects of FcRγ in cancer metastasis, and the results demonstrated that FcRγ deficiency significantly promotes metastasis. The tumor metastasis effect, antiplatelet, platelet or neutrophil infusion experiments were conducted with FcRγ deficient (FcRγ-/-) mice and wild type mice (WT), bearing B16F10 or LCC tumor cells. Blood routine test, flow cytometry, immunofluorescent staining and in vivo image were applied for analysis. Platelet adhesion and neutrophil chemotaxis were analyzed by flow cytometry and ELISA in vitro. Platelet adoptive model was used for mimicing early colonization stage. Our results indicated FcRγ deficiency significantly promoted tumor metastasis accompanied with increased number of platelet and neutrophil in the lung. Further investigation showed that FcRγ-/- platelet infusion, rather than FcRγ-/- neutrophils, promoted CTC colonization. While platelet inhibitor Aspirin abrogated the platelet-mediated infiltration of neutrophil in the lung. Mechanistically, platelet FcRγ deficiency facilitated the adhesion of platelets and cancer cells and increased secretion of CXCL5 and CXCL7 which triggered the platelet-induced neutrophil recruitment. In sum, our study indicates that FcRγ is a restrainer in controlling cancer metastasis through regulating the adhesion of platelets and cancer cells and recruiting more neutrophils, which provides a potential target for anti-metastatic therapies. The level of FcRγ expression in platelets could act as a novel biomarker for cancer metastasis.

In recent years, immunotherapy has shown significant therapeutic potential in patients with advanced tumors. However, only a small number of individuals benefit, mainly due to the tumor microenvironment (TME), which provides conditions for the development of tumors. Macrophages in TME, known as tumor-associated macrophages (TAM), are mainly divided into M1 anti-tumor and M2 pro-tumor phenotypes, which play a regulatory role in various stages of tumorigenesis, promote tumorigenesis and metastasis, and cause immunotherapy resistance.

This review focuses on research strategies and preclinical/clinical research progress in translating TAM into antitumor phenotype by referring to the PubMed database for five years. These include small molecule chemotherapy drug development, metabolic regulation, gene editing, physical stimulation, nanotechnology-mediated combination therapy strategies, and chimeric antigen receptor-based immunotherapy.

It is necessary to explore the surface-specific receptors and cell signaling pathways of TAM further to improve the specificity and targeting of drugs and to strengthen research in the field of probes that can monitor changes in TAM in real time. In addition, the physical stimulation polarization strategy has the advantages of being noninvasive, economical, and stable and will have excellent clinical transformation value in the future.

Proteinase 3 (PRTN3) has been linked to the progression of different cancer types. In this study, the expression and cell biological function of PRTN3 were investigated in gastric cancer (GC) to assess its role in GC progression.

The PRTN3 levels in 20 pairs of GC tissues were detected via quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting, while immunohistochemical staining was used to assess the PRTN3 levels in 47 GC tissue samples. The effects of stable lentivirus-mediated PRTN3 knockdown on GC cell proliferative, cell cycle, and apoptotic activity were evaluated using Cell Counting Kit-8 (CCK-8) and colony formation assays, nude mouse models, and flow cytometry.

Elevated levels of PRTN3 messenger RNA (mRNA) and protein were noted in GC tissues, mostly in the cytosol. High PRTN3 levels were positively correlated with GC tumor N staging. in vitro knockdown of PRTN3 suppressed cell cycle progression, promoted apoptotic induction, and decreased the concentrations of cell cycle-associated proteins (cyclin D1, CDK4, and CDK6) and apoptosis-related Bcl-2 while inducing the upregulation of Bax. Downregulation of PRTN3 inhibited GC cell growth both in vitro and in mouse models.

Our study found that high expression of PRTN3 is associated with GC tumor N staging. And PRTN3 silencing could regulate GC progression by inhibiting the cell cycle and promoting apoptosis in GC cells, which could be a potential target for GC diagnosis and treatment.

Gliomas, a heterogeneous group of tumors affecting the brain and spinal cord, present a significant clinical challenge. Ephrin B1 (EFNB1) has been implicated in various malignancies. However, its role in gliomas remained poorly understood. Hence, this study aimed to elucidate the connection between EFNB1 and the progression of glioma. A retrospective RNA-seq analysis was conducted by utilizing the data from glioma patients in the TCGA and CGGA databases. Kaplan-Meier survival analysis and multivariate regression models were employed to evaluate the prognostic significance of EFNB1. RT-PCR was used to quantify EFNB1 expression in glioma tissues and cell lines. Meanwhile, in vitro assays were carried out to assess its functional roles in glioma cells. Our findings demonstrated that EFNB1 expression was significantly elevated in gliomas and other cancers. Moreover, high EFNB1 expression was closely correlated with advanced clinical stages and poor prognosis. Notably, multivariate analysis identified EFNB1 as an independent prognostic factor for overall survival. KEGG pathway analysis suggested that EFNB1 was involved in critical biological processes, including the cell cycle, protein processing in the endoplasmic reticulum, Epstein-Barr virus infection, and Salmonella infection. Furthermore, EFNB1 expression was associated with immune cell infiltration, particularly Th2 cells, macrophages, and plasmacytoid dendritic cells. In glioma cells, EFNB1 expression was markedly increased. Consequently, functional experiments demonstrated that EFNB1 knockdown inhibited glioma cell proliferation, invasion, and migration. These results highlighted EFNB1 as a novel independent prognostic biomarker and suggest its potential role in shaping the immunological microenvironment of gliomas.

We wished to ascertain if there is an association between neutrophil extracellular traps and endometriosis (EMS). We collected the lesional tissues and normal endometrium of 30 patients suffering from endometriosis. Samples were also taken from healthy controls. Blood from the peripheral circulation was collected to isolate serum and neutrophils. A mouse model of endometriosis was also created. Expression of citrullinated histone and the myeloperoxidase level in tissue were measured by immunofluorescence staining and western blotting. The myeloperoxidase level in peripheral blood serum was measured by enzyme-linked immunosorbent assay. Staining (Trypan Blue) and flow cytometry were used to measure the apoptosis of neutrophils in peripheral blood. BALB/C mice were modeled by allotransplantation, and the experimental parameters noted above quantified. The myeloperoxidase content in the peripheral blood of patients with endometriosis was increased compared with that in healthy controls. Flow cytometry showed that the percent apoptosis of neutrophils in patients with endometriosis was lower than that in healthy controls. Expression of citrullinated histone was higher in the endometriosis group in humans and mice compared with respective controls according to immunofluorescence staining and western blotting. Our data suggest that a high concentration of neutrophil extracellular traps was observed in humans and mice suffering from endometriosis.

Barrett's esophagus (BE) represents a pre-cancerous condition that is characterized by the metaplastic conversion of the squamous esophageal epithelium to a columnar intestinal-like phenotype. BE is the consequence of chronic reflux disease and has a potential progression burden to esophageal adenocarcinoma (EAC). The pathogenesis of BE and EAC has been extensively studied but not completely understood, and it is based on two main hypotheses: "transdifferentiation" and "transcommitment". Omics technologies, thanks to the potentiality of managing huge amounts of genetic and epigenetic data, sequencing the whole genome, have revolutionized the understanding of BE carcinogenesis, paving the way for biomarker development helpful in early diagnosis and risk progression assessment. Genomics and transcriptomics studies, implemented with the most advanced bioinformatics technologies, have brought to light many new risk loci and genomic alterations connected to BE and its progression to EAC, further exploring the complex pathogenesis of the disease. Early mutations of the TP53 gene, together with late aberrations of other oncosuppressor genes (SMAD4 or CKND2A), represent a genetic driving force behind BE. Genomic instability, nonetheless, is the central core of the disease. The implementation of transcriptomic and proteomic analysis, even at the single-cell level, has widened the horizons, complementing the genomic alterations with their transcriptional and translational bond. Increasing interest has been gathered around small circulating genetic traces (circulating-free DNA and micro-RNAs) with a potential role as blood biomarkers. Epigenetic alterations (such as hyper or hypo-methylation) play a meaningful role in esophageal carcinogenesis as well as the study of the tumor micro-environment, which has led to the development of novel immunological therapeutic options. Finally, the esophageal microbiome could be the protagonist to be investigated, deepening our understanding of the subtle association between the host microbiota and tumor development.

Dietary behaviors significantly influence tumor progression, with increasing focus on high-salt diets (HSD) in recent years. Traditionally, HSD has been regarded as a major risk factor for multiple health issues, including hypertension, cardiovascular disease, kidney disease, cancer, and osteoporosis. However, recent studies have uncovered a novel aspect of HSD, suggesting that HSD may inhibit tumor growth in specific pathological conditions by modulating the activity of immune cells that infiltrate tumors and enhancing the effectiveness of PD-1 immunotherapy. This review focused on the duel molecular mechanisms of HSD in cancer development, which are based on the tumor microenvironment, the gut microbiota, and the involvement of sodium transporter channels. The objective of this review is to explore whether HSD could be a potential future oncological therapeutic strategy under specific situation.

Developing nanocarriers that can carry medications directly to tumors is an exciting development in cancer nanomedicine. The efficacy of this intriguing therapeutic approach is, however, compromised by intricate and immunosuppressive circumstances that arise concurrently with the onset of cancer. The artificial antigen presenting cell (aAPC), a micro or nanoparticle based device that mimics an antigen presenting cell by providing crucial signal proteins to T lymphocytes to activate them against cancer, is one cutting-edge method for cancer immunotherapy. This review delves into the critical design considerations for aAPCs, particularly focusing on particle size, shape, and the non-uniform distribution of T cell activating proteins on their surfaces. Adequate surface contact between T cells and aAPCs is essential for activation, prompting engineers to develop nano-aAPCs with microscale contact areas through techniques such as shape modification and nanoparticle clustering. Additionally, we explore recommendations for future advancements in this field.

Despite the recent advancements in the treatment of cancer, the 5-year survival of patients with non-small cell lung cancer (NSCLC) remains unsatisfactory. Lung adenocarcinoma (LUAD) is NSCLC's most common subtype, and metastasis is the major cause of death in patients with cancer. Therefore, identifying novel targets associated with metastasis in NSCLC is crucial to improving treatment. This study aimed to characterize the expression of GNGT1 in LUAD and to clarify the mechanism underlying the association between the higher expression level of GNGT1 and worse prognosis in patients.

The transcriptome datasets and clinical information of patients with LUAD were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. Bioinformatics analyses were performed in 515 patients who were stratified into two groups (high- and low-GNGT1 expression group) according to the GNGT1 level. Overall survival, DNA promotor methylation, immune cell infiltration, gene set enrichment analysis (GSEA), and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to elucidate the functions of GNGT1 and to identify the related hub genes in LUAD. Their expression and functions in LUAD were verified using tissues from patients and transgenic mice overexpressing GNGT1 under the control of a lung-specific promoter (Scgb1a1-Cre).

GNGT1 was overexpressed in patients with LUAD and was associated with poor prognosis. GNGT1 expression was significantly correlated with gene alteration and hypomethylated promoter status. High GNGT1 expression in patients with LUAD was associated with advanced lymph node metastasis and the degree of immune cell infiltration. Functional enrichment analyses indicated that differentially expressed genes (DEGs) in the high-GNGT1 group participated in DNA replication, DNA replication preinitiation, and M phase, while cell adhesion molecules, apoptosis, and natural killer cell-mediated cytotoxicity were all downregulated. Messenger RNA and protein levels were correspondingly regulated in human LUAD tissues and the Scgb1a1-Cre; LSL-GNGT1 mouse model (GNGT1fl/+ mice).

GNGT1 was associated with tumor cell proliferation via the enhancement of tumor cell stemness and interaction with driver genes. Elevated GNGT1 expression promoted epithelial-mesenchymal transformation, remodeled the tumor microenvironment, and led to tumor metastasis, ultimately worsening the survival-related prognosis of patients with LUAD.

Understanding the dynamic tumor immune microenvironment (TIME) is important in guiding immunotherapy. We have previously validated signatures predictive of checkpoint inhibitor efficacy which distinguish immunomodulatory, mesenchymal stem-like, and mesenchymal phenotypes. Here we use twenty tumor types (7162 samples) to identify potentially conserved immune biology within these TIME spaces, genes co-expressed across distinct cell types involved these immune processes, and the association of these signatures with ICI response. One signature, which contained multiple B-cell markers, was associated with immunotherapy efficacy in three cohorts, including IMvigor210. This signature of potentially conserved B-cell biology in co-infiltrated immune cell ecosystems had a more consistent association with outcome than comparable single cell type models and likely reflects a complex immunological response involving multilayered relationships between distinct immune effector cell types. These signatures were most highly expressed in tumors with prominent immune cell invasion, however there was consistent identification of infiltrate presence in relatively immune restricted cases. This suggests that these immune population signatures may identify conserved immune cell type co-infiltrate physiology of the TIME that best captures immune physiology with potential clinical utility.

To study the predictive role of tumor-associated neutrophils in early luminal HER2-negative breast cancer.

This is a retrospective study conducted on 60 women cases aged from 31 to 79 years underwent surgery for luminal HER2-negative ductal breast cancer in tertiary care cancer centre. We first estimated basic morphological signs: tumor size, tumor grade (by Nottingham Histologic Score), tumor infiltrating lymphocytes (TILs), Lymphovascular invasion, hormonal receptors status, proliferative index, and regional lymph nodes metastasis. The expression of intratumoral neutrophils was studied by CD15 immunohistochemistry which was performed using tissue microarrays. The total number of intratumoral neutrophils, were counted in 5 high-power fields.

According to the Nottingham histologic score system, grade I cases were detected in 10 cases (16%), grade II in 34 cases (57%), and grade III in 16 cases (27%). Lymphovascular invasion was determined in 23 cases (38%), and perineural invasion in 14 cases (23%). Number of TILs varied from 0 to 14 (counted in 5 HPF) and averaged 4.2±0.5. Luminal A tumor phenotype was detected in 35 cases (58%), and luminal B HER2-negative in 25 cases (42%). Nineteen (32%) women had metastases in regional lymph nodes (N+). The number of tumor microenvironment neutrophils in luminal HER2-negative breast carcinomas ranged from 1 to 10 (counted in 5 HPF) with an average value of 2.7±0.4. High tumor-associated neutrophils concentration significantly correlated with tumor size (<5mm and >20mm) with p=0.05, high grade (p=0.01), high proliferative index ((r=0.67; p=0.05), TILs (p=0.05), Lymphovascular space invasion (p=0.01)and positive regional lymph nodes metastasis (p=0.001), but not perineural invasion (p=0.1) and also, did not correlate with the expression of estrogen (r=0.18) and progesterone (r=0.14) receptors.

Tumor-associated neutrophils strongly predict a worse prognosis in early luminal HER2-negative breast cancer.

The systemic inflammatory response index (SIRI) is calculated via the following formula: SIRI = monocyte count × neutrophil count/lymphocyte count. The value of the SIRI in predicting the prognosis of gastric cancer (GC) remains controversial. This study revealed the precise effect of the SIRI in predicting GC prognosis through a meta-analysis.

The ability of the SIRI to predict GC prognosis was evaluated by calculating combined hazard ratios (HRs) and 95% confidence intervals (CIs). Furthermore, the combined odds ratios (ORs) and 95% CIs were determined to analyze the associations between the SIRI and the clinicopathological characteristics of patients with GC.

Seven publications on a total of 1763 cases were included in this study. The SIRI threshold was between 0.58 and 1.35, and the median value was 0.85. Our pooled findings revealed that a higher SIRI was significantly linked with poor overall survival (OS) (HR = 1.87, 95% CI = 1.59-2.20, p < 0.001) and disease-free survival (DFS; HR = 1.88, 95% CI = 1.50-2.36, p < 0.001) in GC patients. However, the SIRI did not exhibit a significant association with sex (OR = 1.98, 95% CI = 0.82-4.75, p = 0.126), surgery type (OR = 0.96, 95% CI = 0.61-1.51, p = 0.847), tumor differentiation (OR = 0.75, 95% CI = 0.54-1.06, p = 0.099), or TNM stage (OR = 1.25, 95% CI = 0.34-4.62, p = 0.743) in patients with GC.

An elevated SIRI was significantly associated with unfavorable OS and DFS in patients with GC. Thus, the SIRI is a reliable biomarker for predicting GC prognosis in clinical practice.

Current standard-of-care therapies have failed to improve the survival of patients with metastatic pancreatic cancer (PCA). Therefore, exploring novel therapeutic approaches for cancer targeting is of utmost need. During the past few years, many efforts have been made to develop conventional treatment strategies to reduce chemotherapy resistance. However, critical challenges have impeded current cancer management outcomes, and limited clinical responses have been achieved due to unfavorable off-target effects. Advances in nanotechnology-based gene and immune-modulator delivery systems have excellent advantages for improving the therapeutic efficacy of PCA and provide promising avenues for overcoming the immunosuppressive tumor microenvironment and enhancing patient treatment outcomes. This review article provides insight into the challenges, opportunities, and future perspectives of these novel emerging nanoparticles based on lipid, polymer, and inorganic metal carriers to modulate genes and immunotherapy paradigms for PCA anticancer activity.

At present, there is still a lack of effective treatment strategies for cancer metastasis and drug resistance, so finding effective biomarkers is particularly important. AnnexinA2 (ANXA2), a vital membrane protein, critically influences cancer progression, tumor invasion, and tumor microenvironment modulation. To assess the possible application of ANXA2 as a therapeutic target against cancer cell metastasis and drug resistance to chemotherapeutic drugs in the tumor microenvironment, we elucidated the functionality of ANXA2 in stromal cells, angiogenic vascular cells, and infiltrated immune cells that mediate metastasis and drug resistance, as well as its potential as a therapeutic target. ANXA2 shows a high expression level in many tissues, and its expression level is even higher in several tumors and their microenvironments. ANXA2 is a crucial regulator of many factors and may serve as a target against drug-resistant cancers.

Non-small cell lung cancer (NSCLC) constitutes a significant proportion of lung cancer cases, and despite advancements in treatment modalities, radiotherapy resistance remains a substantial hurdle in effective cancer management. Exosomes, which are small vesicles secreted by cells, have emerged as pivotal players in intercellular communication and influence various biological processes, including cancer progression and the response to therapy. This review discusses the intricate role of exosomes in the modulation of NSCLC radiosensitivity. The paper focuses on NSCLC and highlights how tumor-derived exosomes contribute to radioresistance by enhancing DNA repair, modulating immune responses, and altering the tumor microenvironment. We further explore the potential of mesenchymal stem cell-derived exosomes to overcome radiotherapy resistance and their potential as biomarkers for predicting therapeutic outcomes. Understanding the mechanisms by which exosomes affect radiotherapy can provide new avenues for enhancing treatment efficacy and improving the survival rates of patients with NSCLC.

An increasing number of studies have focused on ailanthone (aila) due to its antitumor activity. However, the role of ailanthone in glioblastoma(GBM) has not been investigated before. This study aims to explore the biological function and the underlying mechanism of ailanthone in GBM.

The microarray analysis was used to screen out down-stream long non-coding RNAs (lncRNAs) targeted by ailanthone. Real-time PCR(RT-PCR) assay was used to examine LINC01956 expression levels. Colony-formation, Methylthiazolyldiphenyl-tetrazolium bromide(MTT), cell-cycle, organoids culture and in-vivo tumorigenesis assays were used to examine cell growth in vitro and in vivo. Boyden assay was used to examine cell invasion ability in vitro. RNA immunoprecipitation and RNA-protein pull-down assays were used to examine the interaction between LINC01956 and FUS protein. Chromatin Immunoprecipitation(ChIP) assay was used to examine HIF1-α-binding sites in the LINC01956 promoter.

Ailanthone decreased GBM cell growth in vitro and in vivo via inducing ferroptosis. Ailanthone treatment exhibited blood‒brain barrier(BBB) permeability and specifically targeted the tumor area. LINC01956 was identified as a down-stream target of Ailanthone. LINC01956 exerted as an onco-lncRNA in GBM. M2 polarization of macrophages induced by exosomes derived from glioma cells overexpressing LINC01956 accelerated GBM progression. Mechanistically, we found that LINC01956 bound to FUS and reduced its ubiquitination. LINC01956 evoked nuclear translocation of phosphorylated (p)-β-catenin by recruiting FUS. Furthermore, under hypoxic conditions, LINC01956 was regulated by HIF-1α. Ailanthone decreased the expression of LINC01956 via suppressing HIF-1α.

Taken together, our data revealed for the first time that ailanthone regulated HIF-1α/LINC01956/FUS/β-catenin signaling pathway and thereby inhibited GBM progression.

The process of cervical lymph node metastasis is dependent on the phenotype of the tumor cells and their interaction with the host microenvironment and immune system; conventional research methods that focus exclusively on tumor cells are limited in their ability to elucidate the metastatic mechanism. In cancer tissues, a specialized environment called the tumor microenvironment (TME) is established around tumor cells, and inflammation in the TME has been reported to be closely associated with the development and progression of many types of cancer and with the response to anticancer therapy. In this study, to elucidate the mechanism of metastasis establishment, including the TME, in the cervical lymph node metastasis of oral cancer, we established a mouse-derived oral squamous cell carcinoma cervical lymph node highly metastatic cell line and generated a syngeneic orthotopic transplantation mouse model. In the established highly metastatic cells, epithelial-mesenchymal transition (EMT) induction was enhanced compared to that in parental cells. In the syngeneic mouse model, lymph node metastasis was observed more frequently in tumors of highly metastatic cells than in parental cells, and Cyclooxygenase-2 (COX-2) expression and lymphatic vessels in primary tumor tissues were increased, suggesting that this model is highly useful. Moreover, in the established highly metastatic cells, EMT induction was enhanced compared to that in the parent cell line, and CCL5 and IL-6 secreted during inflammation further enhanced EMT induction in cancer cells. This suggests the possibility of a synergistic effect between EMT induction and inflammation. This model, which allows for the use of two types of cells with different metastatic and tumor growth potentials, is very useful for oral cancer research involving the interaction between cancer cells and the TME in tumor tissues and for further searching for new therapeutic agents.

Tumor-associated macrophages (TAMs) drive the protumorigenic responses and facilitate tumor progression via matrix remodeling, angiogenesis, and immunosuppression by interacting with extracellular matrix proteins via integrins. However, the expression dynamics of integrin and its correlation with TAM functional programming in the tumors remain unexplored. In this study, we examined surface integrins' role in TAM recruitment and phenotypic programming in a 4T1-induced murine breast tumor model. Our findings show that integrin α5β1 is upregulated in CD11b+Ly6Chi monocytes in the bone marrow and blood by day 10 after tumor induction. Subsequent analysis revealed elevated integrin α5β1 expression on tumor-infiltrating monocytes (Ly6ChiMHC class II [MHCII]low) and M1 TAMs (F4/80+Ly6ClowMHCIIhi), whereas integrin αvβ3 was predominantly expressed on M2 TAMs (F4/80+Ly6ClowMHCIIlow), correlating with higher CD206 and MERTK expression. Gene profiling of cells sorted from murine tumors showed that CD11b+Ly6G-F4/80+α5+ TAMs had elevated inflammatory genes (IL-6, TNF-α, and STAT1/2), whereas CD11b+Ly6G-F4/80+αv+ TAMs exhibited a protumorigenic phenotype (IL-10, Arg1, TGF-β, and STAT3/6). In vitro studies demonstrated that blocking integrin α5 and αv during macrophage differentiation from human peripheral blood monocytes reduced cell spreading and expression of CD206 and CD163 in the presence of specific matrix proteins, fibronectin, and vitronectin. Furthermore, RNA sequencing data analysis (GEO dataset: GSE195857) from bone marrow-derived monocytes and TAMs in 4T1 mammary tumors revealed differential integrin α5 and αv expression and their association with FAK and SRC kinase. In line with this, FAK inhibition during TAM polarization reduced SRC, STAT1, and STAT6 phosphorylation. In conclusion, these findings underscore the crucial role of integrins in TAM recruitment, polarization, and reprogramming in tumors.

Cell death plays an essential role in carcinogenesis, but its function in the recurrence and postoperative prognosis of head and neck cancer (HNC), which ranks as the 7th most common malignancy globally, remains unclear.

Data from five main subtypes of HNC related single-cell RNA sequencing (scRNA-seq) were recruited to establish a single-cell atlas, and the distribution of cell death models (CDMs) across different tissues as well as cell subtypes were analyzed. Bulk RNA-seq from the Cancer Genome Atlas Program (TCGA) dataset was subjected to a machine learning-based integrative procedure for constructing a consensus cell death-related signature risk score (CDRscore) model and validated by external data. The biofunctions including different expression analysis, immune cell infiltration, genomic mutations, enrichment analysis as well as cellchat analysis were compared between the high- and low- risk score groups categorized by this CDRscore model. Finally, samples from laryngeal squamous cell cancer (LSCC) were conducted by spatial transcriptomics (ST) to further validate the results of CDRscore model.

T cells from HNC patients manifested the highest levels of cell death while HPV infection attenuates malignant cell death based on single-cell atlas. CDMs are positively correlated with the tumor-cell stemness, immune-related score and T cells are infiltrated. A CDRscore model was established based on the transcription of ten cell death prognostic genes (MRPL10, DDX19A, NDFIP1, PCMT1, HPRT1, SLC2A3, EFNB2, HK1, BTG3 and MAP2K7). It functions as an independent prognostic factor for overall survival in HNC and displays stable and powerful performance validated by GSE41613 and GSE65858 datasets. Patients in high CDRscore manifested worse overall survival, more active of epithelial mesenchymal transition, TGF-β-related pathways and hypoxia, higher transcription of T cell exhausted markers, and stronger TP53 mutation. ST from LSCC showed that spots with high-risk scores were colocalized with TGF-β and the proliferating malignant cells, additionally, the risk scores have a negative correlation with TCR signaling but positive association with LAG3 transcription.

The CDRscore model could be utilized as a powerful prognostic indicator for HNC.

Macrophages engineered with chimeric antigen receptors (CAR) are suitable for immunotherapy based on their immunomodulatory activity and ability to infiltrate solid tumours. However, the production and application of genetically edited, highly effective, and mass-produced CAR-modified macrophages (CAR-Ms) are challenging.

Here, we used homology-independent targeted insertion (HITI) for site-directed CAR integration into the safe-harbour region of human pluripotent stem cells (hPSCs). This approach, together with a simple differentiation protocol, produced stable and highly effective CAR-Ms without heterogeneity.

These engineered cells phagocytosed cancer cells, leading to significant inhibition of cancer-cell proliferation in vitro and in vivo. Furthermore, the engineered CARs, which incorporated a combination of CD3ζ and Megf10 (referred to as FRP5Mζ), markedly enhanced the antitumour effect of CAR-Ms by promoting M1, but not M2, polarisation. FRP5Mζ promoted M1 polarisation via nuclear factor kappa B (NF-κB), ERK, and STAT1 signalling, and concurrently inhibited STAT3 signalling even under M2 conditions. These features of CAR-Ms modulated the tumour microenvironment by activating inflammatory signalling, inducing M1 polarisation of bystander non-CAR macrophages, and enhancing the infiltration of T cells in cancer spheroids.

Our findings suggest that CAR-Ms have promise as immunotherapeutics. In conclusion, the guided insertion of CAR containing CD3ζ and Megf10 domains is an effective strategy for the immunotherapy of solid tumours.

This work was supported by KRIBB Research Initiative Program Grant (KGM4562431, KGM5282423) and a Korean Fund for Regenerative Medicine (KFRM) grant funded by the Korean government (Ministry of Science and ICT,Ministry of Health and Welfare) (22A0304L1-01).

The effectiveness of Toll-like 9 agonists (CpG) as an adjuvant for tumor immunotherapy is restricted due to their insufficient ability to activate anti-tumor immunity. To address that, the common nutrient metal ions are explored (Mn2+, Cu2+, Ca2+, Mg2+, Zn2+, Fe3+, and Al3+), identifying Mn2+ as a key enhancer of CpG to mediate immune activation by augmenting the STING-NF-κB pathway. Mn2+ and CpG are then self-assembled with epigallocatechin gallate (EGCG) into a nanoadjuvant MPN/CpG. Local delivery of MPN/CpG effectively inhibits tumor growth in a B16 melanoma-bearing mouse model, reshaping the tumor microenvironment (TME) by repolarizing M2-type tumor-associated macrophages (TAMs) to an M1-type and boosting intra-tumoral infiltration of CD8+/CD4+ T lymphocytes and DCs. Furthermore, compared to free CpG, MPN/CpG exhibits heightened accumulation in lymph nodes, enhancing CpG uptake and DC activation, consequently inducing significant antigen-specific cytotoxic CD8+ T cell immune response and humoral immunity. In a prophylactic tumor-bearing mouse model, MPN/CpG vaccination with OVA antigen significantly delays B16-OVA melanoma growth and extends mouse survival. These findings underscore the potential of MPN/CpG as a multifunctional adjuvant platform to drive powerful innate and adaptive immunity and regulate TME against tumors.

Cell adhesion regulates specific migratory patterns, location, communication with other cells, physical interactions with the extracellular matrix, and the establishment of effector programs. Proper immune control of cancer strongly depends on all these events occurring in a highly accurate spatiotemporal sequence. In response to cancer-associated inflammatory signals, effector immune cells navigating the bloodstream shift from their patrolling exploratory migration mode to establish adhesive interactions with vascular endothelial cells. This interaction enables them to extravasate through the blood vessel walls and access the cancer site. Further adhesive interactions within the tumor microenvironment (TME) are crucial for coordinating their distribution in situ and for mounting an effective anti-tumor immune response. In this review, we examine how alterations of adhesion cues in the tumor context favor tumor escape by affecting effector immune cell infiltration and trafficking within the TME. We discuss the mechanisms by which tumors directly modulate immune cell adhesion and migration patterns to affect anti-tumor immunity and favor tumor evasion. We also explore indirect immune escape mechanisms that involve modifications of TME characteristics, such as vascularization, immunogenicity, and structural topography. Finally, we highlight the significance of these aspects in designing more effective drug treatments and cellular immunotherapies.

Background: Follicular lymphoma (FL) presents significant clinical heterogeneity, with some patients experiencing transformation into an aggressive disease, a key contributor to FL-related mortality. Based on gene expression profiles, this study aimed to provide insights into immunological differences associated with transformation. Methods: Gene expression analysis using the NanoString nCounter Tumor Signaling 360 Panel was performed on diagnostic lymphoma samples from 70 FL patients diagnosed in the rituximab era, either non-transforming FL (nt-FL, n = 34) or subsequently transforming FL (st-FL, n = 36), with paired high-grade transformed FL (tFL, n = 36) samples available. In silico immunophenotyping was performed to infer immune cell infiltration using the CIBERSORTx algorithm. Results: The gene expression analysis revealed 164 significantly differentially expressed genes, distinguishing st-FL from nt-FL and generally presenting an upregulation of B cell-related genes (CD40, IRF4, RELB), immunosuppressive molecules (IL10, SOCS3), and immune checkpoint molecules (CD276, TIM3). Analysis of immune cell proportions indicated significant differences in infiltrates of M1-like macrophages (p = 0.007) and neutrophils (p = 0.012) in nt-FL versus st-FL samples. Transformation-free survival (TFS) was associated with high numbers of both these cellular subsets (p = 0.006 and 0 = 0.002, respectively). This was even more evident when combined with inferior TFS in lymphomas with high infiltrates of both cell types (p < 0.001). After transformation, tFL samples showed a reduction in T follicular helper cells (p = 0.008) and an increase in immunosuppressive M2-like macrophages and neutrophils (p < 0.001 and p = 0.028, respectively). Conclusion: By elucidating the distinct molecular and immune landscapes of FL at the time of diagnosis and transformation, this study underscores the importance of immune microenvironment in FL transformation and patient outcome.

Mitochondrial dysfunction, a hallmark of immune cell failure, affects the antitumor effects of immune cells through metabolic reprogramming, fission, fusion, biogenesis, and immune checkpoint signal transduction of mitochondria. According to researchers, restoring damaged mitochondrial function can enhance the efficacy of immune cells. Nevertheless, the mechanism of mitochondrial dysfunction in immune cells in patients with cancer is unclear. In this review, we recapitulate the impact of mitochondrial dysfunction on the antitumor effects of T cells, natural killer cells, dendritic cells, and tumor-associated macrophage and propose that targeting mitochondria can provide new strategies for antitumor therapy.