Search Results (925)

Background: Intrahepatic cholangiocarcinoma (ICC) has a poor prognosis due to late-stage presentation and ineffective systemic therapies. Targeting the tumor microenvironment (TME) in ICC offers new therapeutic possibilities, particularly through tumor-associated macrophages (TAM), which can both promote and inhibit tumor progression. The current study utilized multi-omics analysis to characterize the gene signature of TAM and explore its therapeutic potential in ICC. Methods: Public GEO datasets provided the basis for analysis. Single-cell RNA sequencing (scRNA-seq) data from five ICCs, three adjacent non-tumorous tissues (ANTs), and four healthy liver samples were examined with Python. To validate scRNA-seq findings, bulk RNA-seq data from 27 ICC and 27 matched ANT samples were assessed using R. Differentially expressed genes were identified with adjusted p-values <0.01 and log2-fold changes >1 or <−1. CIBERSORT pipeline analyzed 22 immune cell subtypes in bulk RNA-seq data. STRING database analyzed the contribution of unique TAM-related genes to networks of protein–protein interactions. Results: TAM population demonstrated phenotypic heterogeneity exhibiting partial gene signatures of inflammatory (MS1) and anti-inflammatory (MS2) macrophages. Unique TAM-associated markers, TREM2, CD9, and PRMT10, showed variable expression within the TAM subpopulation. Bulk RNAseq analysis confirmed the scRNA-seq results, highlighting overexpression of TREM2 and CD9 in most ICC samples versus ANT. Immune cell deconvolution revealed decreased MS1 and MS2 macrophages in ICC, and alterations in adaptive immune profile, suggesting immunotolerant TME. STRING database defined TREM2-LGALS3 axis as a potential target for anti-tumor therapies. Conclusions: TAM represents a unique heterogenous population which is primarily found in ICC TME versus ANT or healthy liver tissue The non-uniform expression of unique gene signature demonstrates additional heterogeneity in the TAM subpopulation and suggests that TREM2+ TAM may be desirable targets for anti-TREM2-LGALS3 immunotherapy. Full article

Hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors, clinically established for treating renal anemia, are emerging as potent immunomodulators with therapeutic potential far beyond erythropoiesis. This review dissects the mechanistic basis of their action, centered on the stabilization of hypoxia-inducible factor-alpha (HIF-α), a master transcription factor that orchestrates fundamental shifts in immune cell function. We synthesize evidence showing how HIF-α stabilization alters innate immunity, recalibrates T- and B-cell responses, and reshapes inflammatory signaling. This activity translates to significant efficacy in preclinical models of autoimmune disorders, organ fibrosis, and ischemia–reperfusion injury. However, their broader clinical translation is hindered by a critical paradox in oncology. While HIF-α can potentiate anti-tumor immunity, its sustained activation risks promoting malignancy by driving angiogenesis, metabolic reprogramming, and fostering an immunosuppressive tumor microenvironment. Addressing this duality, alongside the potential for long-term immune dysregulation, is paramount. Future development must therefore prioritize precision-targeting strategies to harness the therapeutic benefits of HIF-PHD inhibitors while mitigating their pro-tumorigenic liabilities. Full article

The inflammatory milieu surrounding tumors plays a pivotal yet paradoxical role in promoting carcinogenesis. Rather than simply acting as a host defense mechanism, chronic low-grade inflammation actively nurtures tumor development and supports hallmarks such as sustained proliferative signaling, apoptosis resistance, angiogenesis, and metastasis. Obesity, characterized by a chronic inflammatory state, exacerbates this tumor-promoting environment through metabolic imbalances like insulin resistance, hyperglycemia, and dyslipidemia. These conditions stimulate oncogenic signaling pathways and reshape the tumor microenvironment. Obesity-associated cytokines, altered adipokines, and insulin-related growth signals synergistically enhance processes such as epithelial-to-mesenchymal transition (EMT) and matrix remodeling. This review explores the mechanistic interplay between obesity-induced inflammation and insulin resistance in cancer progression, discusses the molecular pathways involved, and highlights emerging therapeutic approaches targeting these intersecting tumor promotion axes. Full article

Hypoxia is a hallmark of solid tumors, driving metabolic reprogramming and immune evasion. In lung cancer, hypoxia-induced activation of carbonic anhydrase IX (CAIX) promotes lactate accumulation and extracellular acidification, fostering an immunosuppressive tumor microenvironment (TME). Analysis of public datasets revealed that patients with high CAIX expression exhibited significantly reduced median survival (p < 0.001). Moreover, CAIX correlated with HIF-1α, PD-L1, and immunosuppressant molecules, linking hypoxia-driven metabolic alterations with immune dysfunction. Here, we evaluated the capacity of 4-methylumbelliferone (4Mu) to counteract these effects and enhance antitumor immunity. In vitro, hypoxia increased CAIX and monocarboxylate transporter -4 (MCT4) expression in lung carcinoma cells, elevated lactate release, and reduced extracellular pH while promoting an M2-like macrophage profile and impairing antigen-specific splenocyte proliferation (p < 0.01). Treatment with 4Mu downregulated CAIX expression, restored extracellular pH, decreased lactate secretion, and rescued lymphocyte proliferation (p < 0.01). In vivo, 4Mu reduced CAIX expression, shifted macrophage polarization toward a pro-inflammatory phenotype, and enhanced CD8+ T cell infiltration. 4Mu was safe and well tolerated, and notably, combined with anti-PD-1 therapy, it synergistically inhibited tumor growth and increased both CD4+ and CD8+ T cell infiltration. These findings support 4Mu as a metabolic modulator capable of mitigating CAIX-driven acidosis and improving the efficacy of immunotherapy in lung cancer. Full article

Background and Objectives: S100A8 regulates inflammatory responses and immune cell activation and is overexpressed in several solid tumors. However, its clinicopathological significance in endometrial carcinoma (EC) remains unclear. This study aimed to evaluate the expression patterns of S100A8 in both tumor and immune cells of EC and examine its association with clinicopathological features. Materials and Methods: Fifty-two formalin-fixed, paraffin-embedded EC specimens were analyzed using tissue microarray-based immunohistochemistry. S100A8 expression was assessed in tumor and immune cells. The tumor proportion score (TPS), tumor staining intensity (TI), and immune proportion score (IPS) were dichotomized into low and high categories (TPS/IPS: ≤30% vs. ≥31%; TI: 0–1+ vs. 2–3+). Correlations with clinicopathological parameters were examined using the chi-square and Fisher’s exact tests. Results: A low TPS, high TI, and high IPS were observed in 51.9%, 63.5%, and 57.7% of patients, respectively. TPS and TI showed no significant correlation with clinicopathological variables, including age, tumor size, invasion depth, histologic grade, T stage, and N stage (all p > 0.05). By contrast, IPS was significantly associated with patients’ age (p = 0.044) and histologic grade (p = 0.012), with older patients and those with higher-grade tumors demonstrating a higher IPS. A positive correlation was observed between TPS and IPS (p = 0.044), whereas TI did not correlate with IPS (p = 0.253). Conclusions: S100A8 expression in immune cells, but not in tumor cells, is associated with age and tumor grade in EC. Therefore, immune-related S100A8 expression may serve as a biomarker of the tumor immune microenvironment, warranting further investigation into its prognostic and therapeutic implications. Full article

To enhance the nutritional value of sheep fat, high-melting-point solid fat (HSO) and low-melting-point liquid oil (LSO) were prepared from Altay sheep rump fat via solvent fractionation. The effects of HSO and LSO on lipid metabolism and intestinal health were evaluated in a mouse model. Results showed that HSO, rich in saturated fatty acids (SFA), induced obesity, dyslipidemia, and colonic inflammation in mice. These adverse effects were associated with the upregulation of hepatic lipid synthesis genes such as Sterol regulatory element-binding protein 1c (SREBP-1c) and Fatty acid synthase (FAS), as well as increased expression of pro-inflammatory cytokines including Tumor necrosis factor-alpha (TNF-α) and Interleukin-6 (IL-6) in the colon. In contrast, LSO, which was predominantly composed of unsaturated fatty acids (UFA), did not cause significant metabolic disorders. Instead, it promoted the upregulation of fatty acid oxidation-related genes such as Peroxisome proliferator-activated receptor alpha (PPARα) and Acyl-CoA oxidase 1 (Acox1), helped maintain intestinal microbial balance, and enhanced the production of beneficial short-chain fatty acids (SCFAs), particularly butyrate and propionate. In conclusion, solvent fractionation effectively modulates the fatty acid composition of sheep fat, thereby influencing lipid metabolism and inflammatory responses through the regulation of key gene expression and modulation of the gut microenvironment. Full article

Hepatocellular carcinoma (HCC) is the most prevalent primary malignancy of the liver. Characterized by rapid progression and poor overall survival rates, HCC requires effective and streamlined treatment regimens. It predominantly occurs in East Asia and sub-Saharan Africa, where it has historically been managed with herbal formulas. We previously observed that the herbal formula HO-1089 exerts potent anti-HCC effects both in vitro and in vivo. In this study, we investigated the anticancer efficacy and mechanisms of HO-1197, a reconstituted herbal formulation derived from HO-1089. HO-1197 selectively inhibited the viability of HCC cell lines without hepatotoxicity and demonstrated superior anticancer activity compared with both HO-1089 and sorafenib. Mechanistically, HO-1197 induced apoptosis and G2/M arrest through reactive oxygen species-mediated DNA damage, independent of p53 status. Transcriptomic analysis revealed downregulation of mitosis-related genes, particularly those regulated by FOXM1, a key driver of HCC proliferation and metastasis. HO-1197 suppressed FOXM1 expression and nuclear translocation, reducing its downstream targets and diminishing angiogenic and metastatic potential. Furthermore, HO-1197 modulated the tumor immune microenvironment by promoting pro-inflammatory macrophage polarization and enhancing natural killer cell-mediated cytotoxicity. HO-1197 exhibited potent antitumor efficacy, and combination therapy with HO-1197 and sorafenib exhibited synergistic effects in both two-dimensional and immune-activated multicellular spheroid models. These findings suggest that HO-1197 is a promising multifunctional therapeutic candidate with antitumor, antiangiogenic, antimetastatic, and immunomodulatory properties. Its combination with sorafenib may offer effective treatment for HCC. HO-1197, which demonstrated strong efficacy, is a novel herbal medicine developed by H&O Biosis and is referred to as an Integrated Natural Medicine. Full article

In the past decade, research on recombinant oncolytic viral agents in the treatment of solid tumors has evolved from the initial stage of simple genetic engineering to the current stage of multiple pipelines of parallel clinical application and combination therapy. Compared with T-VEC, the classical therapeutic agent that only expresses GM-CSF, which was approved in 2015, most new oncolytic virus designs include diverse gene constructs to reduce toxic effects, enhance multiple antitumor immunity, avoid immune clearance, or enhance tumor targeting. The single route of administration that activates the inflammatory tumor immune microenvironment by intratumoral injection is no longer sufficient to meet the treatment needs of refractory solid tumors. In this review, we illustrated the construction patterns of typical recombinant oncolytic viral agents and their latest clinical trial progress. Secondly, we summarized the underlying mechanisms of the combined application of antiviral and antitumor immunity in the field of solid tumor immunotherapy. Finally, we explored the feasibility of the intravenous application of oncolytic viruses and their future development directions. We believe that the diversified treatment design of oncolytic viruses will bring more surprises to the immunotherapy of refractory tumors. Full article

Fusobacterium nucleatum is a Gram-negative anaerobe that occupies a central ecological niche in oral biofilms but has emerged as a trans-compartmental pathogen implicated in gastrointestinal and cardiovascular diseases. In inflammatory bowel diseases, Fusobacterium nucleatum adheres to the intestinal epithelium via adhesins such as FadA, disrupts tight junctions, and induces Toll-like receptor–mediated inflammatory cascades, amplifying epithelial permeability and sustaining mucosal inflammation. In colorectal cancer, Fusobacterium nucleatum promotes carcinogenesis through multiple mechanisms, including β-catenin activation, modulation of oncogenic microRNAs, and immune evasion via Fap2–TIGIT signaling, while also fostering a pro-inflammatory and immunosuppressive tumor microenvironment. Its enrichment correlates with advanced tumor stage, chemoresistance, and poor prognosis, underscoring its potential as a biomarker and therapeutic target. Beyond the gut, Fusobacterium nucleatum has been detected in atherosclerotic plaques and endocardial tissues, where it contributes to endothelial dysfunction, foam cell formation, oxidative stress, and plaque instability, thereby linking chronic oral infection with cardiovascular risk. Collectively, evidence suggests that Fusobacterium nucleatum acts as a pathophysiological connector across IBD, CRC, and CVD through conserved mechanisms of adhesion, immune modulation, and inflammation. Understanding these processes provides opportunities for innovative interventions, ranging from targeted antimicrobials and host-directed therapies to dietary and microbiome-based strategies, aimed at mitigating the systemic burden of this organism and improving clinical outcomes across multiple diseases. Full article

Periodontal disease (PD), a chronic inflammatory condition driven by oral microbial dysbiosis, is increasingly implicated in systemic diseases, including colorectal cancer (CRC). The “red complex” bacteria—Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola—play a central role in PD progression and exhibit virulence factors that promote inflammation, immune evasion, and epithelial colonization. A literature search in PubMed, Google Scholar, and ScienceDirect (English and Slovenian, up to September 2025) identified 12 eligible studies. Only original clinical, in vivo, or in vitro research directly addressing red complex pathogens and colorectal cancer was included. The search results showed that most of the literature focuses on the association between Porphyromonas gingivalis and CRC, particularly its role in tumor immune evasion, alteration of the gut microbiota, creation of a pro-inflammatory microenvironment, and promotion of carcinoma cell proliferation. Infection with Porphyromonas gingivalis has also been linked to poorer cancer prognosis. The other red complex bacteria are primarily mentioned in the context of generating a pro-inflammatory microenvironment and contributing to chronic inflammation, which supports tumor growth and survival. Full article

The design of innovative compounds displaying anti-inflammatory activity in oncological context is a subject of great interest in drug development. It has been proved that a pro-inflammatory microenvironment which accelerates cancer growth and cellular differentiation is often present in malignant bladder tumor. In earlier work, we reported the synthesis of p-aminobenzoic acid derivatives that act as anti-inflammatory compounds able to inhibit the pro-inflammatory markers present in bladder cancer microenvironment. DAB-1 rapidly emerged as an effective lead candidate in this investigation, with its ability to shrink by 90% in 25 days the size of human bladder cancer tumors in an ectopic mouse model. This manuscript discloses the synthesis of 23 new hydrazide derivatives of DAB-1 and reports their in vitro and in vivo biological evaluation. It was discovered that most of the new compounds are essentially nontoxic against RAW 264.7 cells, as evaluated by an MTT assay. Anti-inflammatory activity of the new derivatives was investigated by evaluation of their impact on cellular nitric oxide production, measured by a Griess assay. Some compounds did significatively inhibit nitric oxide production much more effectively than the original DAB-1. Striking activity of 14, which is around four times more potent than DAB-1, promotes this derivative as new lead compound in this study. The study of these analogs reveals that a phenolic/anisole core is a key component to achieve high biological activity. Furthermore, mice models of acute inflammation and invasive BCa tumors were used to assess the in vivo impact of derivative 14, and it was found that this compound does reduce inflammation in these mice, possess similar anti-inflammatory activity but higher anti-tumoral activity compared to DAB-1 with no apparent signs of toxicity. Full article

Background: Tumor-associated macrophages (TAMs) are essential regulators of the glioblastoma (GBM) microenvironment; their functional heterogeneity and interaction networks are not fully elucidated. We identify RNF135 as a novel TAM-enriched gene associated with immune activation and adverse prognosis in GBM. Methods: To evaluate RNF135’s expression profile, prognostic significance, and functional pathways, extensive transcriptome analyses from TCGA and CGGA cohorts were conducted. The immunological landscape and cellular origin of RNF135 were outlined using single-cell RNA-seq analyses and bulk RNA-seq immune deconvolution (MCP-counter, xCell and ssGSEA). Cell–cell communication networks between tumor cells and RNF135-positive and -negative tumor-associated macrophage subsets were mapped using CellChat. Results: RNF135 predicted a poor overall survival and was markedly upregulated in GBM tissues. Functional enrichment analyses showed that increased cytokine signaling, interferon response, and innate immune activation were characteristics of RNF135-high samples. Immune infiltration profiling showed a strong correlation between the abundance of T cells and macrophages and RNF135 expression. According to the single-cell analyses, RNF135 was primarily expressed in TAMs, specifically in proliferation, phagocytic, and transitional subtypes. RNF135-positive TAMs demonstrated significantly improved intercellular communication with aggressive tumor subtypes in comparison to RNF135-negative TAMs. This was facilitated by upregulated signaling pathways such as MHC-II, CD39, ApoE, and most notably, the CCL signaling axis. The CCL3/CCL3L3–CCR1 ligand–receptor pair was identified as a major mechanistic driver of TAM–TAM crosstalk. High RNF135 expression was also linked to greater sensitivity to Selumetinib, a selective MEK1/2 inhibitor that targets the MAPK/ERK pathway, according to drug sensitivity analysis. Conclusions: RNF135 defines a TAM phenotype in GBM that is both immunologically active and immunosuppressive. This phenotype promotes inflammatory signaling and communication between cells in the tumor microenvironment. Targeting the CCL–CCR1 axis or combining RNF135-guided immunomodulation with certain inhibitors could be a promising therapeutic strategies for GBM. Full article

The morphogenesis of the primordial gut relies on signaling pathways such as Wnt, FGF, Notch, Hedgehog, and Hippo. Reciprocal crosstalk between the endoderm and mesoderm is integrated into the signaling pathways, resulting in craniocaudal patterning. These pathways are also involved in adult intestinal homeostasis including cell proliferation and specification of cell fate. Perturbations in this process can cause growth disturbances manifesting as adenomas, serrated lesions, and cancer. Significant differences have been observed between right and left colon cancers in the hindgut, and between the jejunoileum, appendix, and right colon in the midgut. The question is to what extent the embryology of the mid- and hindgut contributes to differences in the underlying tumor biology. This review examines the precursor lesions and consensus molecular subtypes (CMS) of colorectal cancer (CRC) to highlight the significance of embryology and tumor microenvironment (TME) in CRC. The three main precursor lesions, i.e., adenomas, serrated lesions, and inflammatory bowel disease-associated dysplasia, are linked to the CMS classification, which is based on transcriptomic profiling and clinical features. Both embryologic and micro-environmental underpinnings of the mid- and hindgut contribute to the differences in the tumors arising from them, and they may do so by recapitulating embryonic signaling cascades. This manifests in the range of CRC CMS and histologic cancer subtypes and in tumors that show multidirectional differentiation, the so-called stem cell carcinomas. Emerging evidence shows the limitations of CMS particularly in patients on systemic therapy who develop drug resistance. The focus is thus transitioning from CMS to specific components of the TME. Full article

Background/Objectives: Omentin, also known as intelectin-1, is a secreted adipokine with anti-inflammatory, insulin-sensitizing, and immune-modulatory functions, primarily expressed in visceral adipose tissue. While omentin has been associated with favorable metabolic outcomes, its role in cancer pathogenesis appears context-dependent and remains poorly understood. This review investigates the biological functions, expression patterns, and clinical relevance of omentin across gastrointestinal malignancies. Methods: A comprehensive review of the literature was conducted using PubMed, Scopus, and Web of Science up to August 2025 to evaluate the role of omentin in gastrointestinal cancers. Both preclinical and clinical studies evaluating omentin, its analogues and omentin-enhancing agents in gastric, colorectal, hepatic, pancreatic, and esophageal cancers were included. Results: Omentin exhibits anti-proliferative, anti-inflammatory, and anti-angiogenic effects within the tumor microenvironment in several GI malignancies. However, evidence also indicates a dual role. High intratumoral omentin expression correlates with improved prognosis in colorectal, gastric, and hepatic cancers; in contrast, elevated circulating levels–particularly in colorectal and pancreatic cancers–have been paradoxically associated with increased cancer risk and poor outcomes. Mechanistically, omentin modulates PI3K/Akt, NF-κB, AMPK, and oxidative stress pathways, and interacts with TMEM207. However, most available studies are small-scale and heterogeneous, with methodological inconsistencies and limited multi-omics integration, leaving major knowledge gaps. Conclusions: This review highlights omentin’s distinct systemic and local roles across GI cancers, underscoring its translational implications. Omentin emerges as a promising but context-dependent biomarker and therapeutic target, with future research needed to address heterogeneity, standardize assays, and validate its clinical utility in large-scale prospective studies. Full article

Background/Objectives: The interaction between brain-metastasizing melanoma cells and surrounding microglia shapes the immune tumor microenvironment and influences tumor progression. Gene expression analysis revealed that sphingosine-1-phosphate receptor 1 (S1PR1), encoding the S1P1 receptor, is upregulated in microglia upon interaction with melanoma cells. Here, we investigated the functions of S1P1 in microglia and its contribution to melanoma–microglia crosstalk. Methods: We examined the effects of S1P1 inhibition on microglia and four brain-metastasizing human melanoma cell lines in monocultures and co-cultures using the selective S1P1 antagonist NIBR0213 and S1PR1 gene knockdown. Results: We found that melanoma-secreted IL-6 upregulated S1PR1 expression in microglia. S1P1 inhibition increased expression of CD32, CD150, and CD163 in microglia; however, CD150 and CD163 upregulation was abolished in the presence of melanoma cells. S1P1 inhibition downregulated immunosuppressive and anti-inflammatory factors in microglia, including CD274, SOCS3, TGFBR1, TGFBR2, and JunB, promoting a pro-inflammatory phenotype. It also reduced viability of both melanoma and microglia cells, inducing apoptosis in melanoma-associated microglia, possibly via downregulation of CH25H, an upstream regulator of SREBPs. In co-cultures, melanoma cells were more sensitive than microglia to NIBR0213-induced growth arrest. In 3D spheroid cultures, NIBR0213 delayed melanoma–microglia aggregation. Combined treatment with the BRAF inhibitor Vemurafenib and NIBR0213 enhanced Vemurafenib efficacy in three of four melanoma lines. Conclusions: S1P1 contributes to the immunosuppressive phenotype of microglia. Inhibiting the S1P/S1P1 axis impairs viability and crosstalk between melanoma cells and tumor-activated microglia, offering a potential therapeutic strategy for melanoma brain metastases. Full article