Search Results (20,077)

Hepatocellular carcinoma (HCC) remains a major global health challenge and one of the leading causes of cancer-related mortality, with advanced disease continuing to be associated with limited therapeutic options and substantial heterogeneity in response to systemic treatment. Recent evidence has established the gut microbiota, through the gut–liver axis, as a critical determinant of immunotherapy efficacy, while also influencing antitumor immunity and liver carcinogenesis. Microbial dysbiosis may promote chronic inflammation, intestinal barrier disruption, bacterial translocation, and immune dysfunction, thereby contributing to hepatocarcinogenesis. Moreover, gut microbial composition and microbial-derived metabolites, including bile acids, short-chain fatty acids (SCFAs), and inosine, have been associated with modulation of antitumor immune responses and differential outcomes to immune checkpoint inhibitors (ICIs). Emerging clinical evidence in HCC has identified distinct gut microbial signatures associated with response to nivolumab, pembrolizumab, and atezolizumab-based regimens, including enrichment of Akkermansia muciniphila and SCFA-producing taxa such as Ruminococcaceae, Roseburia, and Prevotella in responders. However, these findings remain inconsistent across studies, with no reproducible microbial signature identified because of small cohort sizes, heterogeneous patient populations, geographic variation, cirrhosis-related confounding factors, and methodological differences in microbiome analysis. This review summarizes the current understanding of microbiome–immune interactions in HCC, examines mechanistic pathways linking the microbiota to immunotherapy response, critically evaluates available clinical evidence, and discusses current limitations and future therapeutic strategies, including fecal microbiota transplantation, probiotics, dietary modulation, and engineered bacterial platforms. Collectively, microbiome-based approaches may contribute to the development of personalized immunotherapeutic strategies in HCC, although larger standardized prospective studies are required before microbiome-derived biomarkers can be implemented in routine clinical practice. Full article

Background/Objectives: The health-protective properties of olive oil phenolics, including their potential chemopreventive and anticancer effects, have attracted considerable scientific interest. However, their in vivo efficacy and mechanisms of action remain insufficiently understood. Recent advances in extraction and purification technologies have enabled large-scale production of highly purified olive oil phenols and phenolic-rich extracts, facilitating translational research. Methods: Herein, the antitumor efficacy of isolated olive oil phenols and phenolic-rich formulations was investigated in an MDA-MB-231 triple-negative breast cancer (TNBC) xenograft model. Results: Intraperitoneal administration of oleocanthal (OLC), oleuropein aglycone (OleA) or their combination reduced endpoint tumor burden, with OLC exhibiting the most pronounced effect. Oral administration of total olive oil phenolics (OOPs) achieved comparable efficacy. Pre-treatment initiated before tumor cell implantation conferred the greatest protection, consistent with a prophylactic mode of action. In contrast, delayed intervention displayed diminished or no antitumor benefit. Phenolic-rich extra virgin olive oil likewise showed an inhibition trend in tumor progression. Mechanistically, OOPs attenuated plasma protein oxidation, modulated proteasome mediated proteolysis, and reduced γH2AX levels in vivo. Furthermore, OOPs negatively affected the MDA-MB-231 cell migration in a concentration-dependent manner in vitro. Conclusions: Collectively, these findings are consistent with antitumor activities of olive oil phenolics via multiple mechanisms and support their further investigation as prophylactic agents in TNBC and as nutraceuticals. Full article

Background/Objectives: Breast cancer is the most frequently diagnosed cancer among women worldwide and a leading cause of cancer-related death. Despite the use of bisphosphonates, RANKL inhibitors, chemotherapy, and available endocrine therapies, the five-year survival rate for patients with bone metastases remains approximately 20–30%, underscoring the urgent need for novel, metastasis-specific therapeutic strategies. Recent studies demonstrated that miR-10b can serve as an attractive therapeutic target for the treatment of metastatic breast cancer, particularly in the context of bone metastasis. This study aimed to test antimir-10b therapeutics in a mouse model of breast cancer bone metastasis. Methods: We utilized a previously developed dextran-coated iron oxide nanoparticle-based platform for delivery of antisense anti-miR-10b oligonucleotides to bone metastases. The magnetic properties of the nanoparticles allowed for in vivo imaging of therapeutic delivery to metastatic tumors. Results: We showed the delivery of the therapeutics in the bone colonization model by in vivo imaging as well as significant survival benefits in injected animals. There was a significant inhibition of miR-10b following treatment that resulted in significant upregulation of the downstream target HOXD10 in vitro and a similar trend in vivo. Repeated dosing of the therapeutics was well tolerated, and no systemic toxicity was observed, supporting the safety profile of this approach. Conclusions: Collectively, these studies demonstrated that targeting miR-10b using an image-guided anti-miR-10b nanotherapeutic represents a promising and translatable strategy for targeting breast cancer bone metastases. Full article

Genistein (GEN) exhibits concentration- and cell-type-dependent biological activities; however, the mechanisms underlying its cytotoxicity remain incompletely understood. This study investigated whether oxidative stress-mediated mitochondrial dysfunction contributes to GEN-induced apoptosis in TM4 mouse Sertoli cells and ELT3 rat leiomyoma cells. Cells were exposed to GEN (30 or 100 µM) for 48 h. Cytotoxicity, oxidative stress, mitochondrial function, and apoptosis were assessed by measuring cell viability, lactate dehydrogenase release, reactive oxygen species (ROS), malondialdehyde, glutathione reductase activity, mitochondrial membrane potential (ΔΨm), intracellular ATP, apoptosis-related gene expression, and caspase-3/-9 activities. The involvement of oxidative stress was examined using N-acetyl-L-cysteine (NAC). GEN reduced cell viability, antioxidant capacity, ΔΨm, and ATP content while increasing membrane damage, ROS accumulation, and lipid peroxidation in both cell lines. These changes were accompanied by upregulation of Bax, Tp53, caspase-3, and caspase-9; downregulation of Bcl-2; and increased caspase-3/-9 activities. NAC pretreatment attenuated these alterations, supporting ROS as an upstream mediator. Notably, TM4 cells were approximately 4.4-fold more sensitive to GEN than ELT3 cells at 48 h. Collectively, the findings support a ROS-dependent mitochondrial apoptotic response under elevated in vitro GEN exposure but do not establish selective antitumor cytotoxicity or direct physiological relevance. Full article

Background/Objectives: The inflammatory burden index (IBI), calculated as C-reactive protein (CRP) multiplied by the neutrophil-to-lymphocyte ratio (NLR), has demonstrated prognostic value across several solid tumors. Its role in breast cancer, however, has not been investigated. This study evaluated whether pretreatment or post-treatment IBI could predict pathological complete response (pCR) in patients with HER2-positive or triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy (NAC). Methods: This single-center retrospective study included 61 patients who completed NAC followed by surgery between 2019 and 2025. IBI was calculated before and after NAC, and the treatment-related change (ΔIBI) was assessed. Conventional inflammatory indices, including NLR, platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), C-reactive protein-to-albumin ratio (CAR), and absolute lymphocyte count (ALC), were evaluated for comparison. Analyses included Mann–Whitney U tests, paired Wilcoxon signed-rank tests, receiver operating characteristic (ROC) curve analysis, and multivariable logistic regression. Results: Twenty-nine patients (47.5%) achieved pCR. No pretreatment or post-treatment inflammatory index was significantly associated with pCR. In paired within-patient analysis, IBI increased significantly during treatment only in patients achieving pCR (p = 0.036), while remaining unchanged in the non-pCR group (p = 0.627). CAR showed an identical pattern, increasing exclusively in the pCR group (p = 0.013). This selective rise was not observed for any index lacking a CRP component and was independent of molecular subtype, anti-HER2 therapy, and chemotherapy regimen. On ROC analysis, ΔCAR yielded the highest area under the curve (AUC) among all inflammatory indices (0.637; p = 0.067), followed by ΔIBI (0.606; p = 0.157); neither reached statistical significance. Ki-67 was the only independent predictor of pCR (AUC 0.724; p = 0.003; optimal cutoff ≥25%). Conclusions: This is the first study to evaluate IBI in HER2-positive and TNBC receiving NAC. Static IBI values did not predict pCR. The selective rise in IBI and CAR during treatment in patients achieving pCR—two independently formulated CRP-based indices showing an identical pattern—suggests that the CRP component carries the biologically relevant signal. This hypothesis-generating observation warrants prospective validation in larger cohorts. Full article

Dysregulation of the kynurenine pathway (KYNP) is increasingly recognized as a hallmark of cancer-associated metabolic reprogramming, contributing to immune evasion, oxidative stress, and tumor progression through the activity of enzymes such as indoleamine 2,3-dioxygenase 1 (IDO1), indoleamine 2,3-dioxygenase 2 (IDO2), and tryptophan 2,3-dioxygenase (TDO2). This systematic review aimed to evaluate the current evidence on the ability of phytochemicals to modulate the KYNP and their potential implications for cancer prevention and therapy. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and included English-language articles and book chapters published between 2016 and 2026 that were retrieved from the Scopus and PubMed databases. A keyword co-occurrence network was generated using VOSviewer (v1.6.20) based on the complete Scopus and PubMed exports of the included studies to identify major research themes. The available evidence indicates that phytochemicals restore anticancer immunity by targeting multiple components of the KYNP, including inhibition of IDO1-mediated kynurenine production and suppression of downstream aryl hydrocarbon receptor signalling, thereby enhancing cytotoxic T-cell responses, reducing immunosuppressive cell populations, and improving antitumor immune activity. Collectively, these findings support the KYNP as a promising immunometabolic target and highlight phytochemicals as potential complementary agents for cancer immunotherapy while emphasizing the need for further investigation of the biological and immunological roles of IDO2. Full article

Enhydrin, a melampolide-type sesquiterpene lactone abundant in the leaves of yacon (Smallanthus sonchifolius), has not previously been investigated for its anti-prostate cancer activity. This study investigated the antiproliferative effects of enhydrin in human prostate cancer cells, its regulatory effects on apoptosis-related molecules, and its impact on the PI3K/AKT and NF-κB signaling pathways. Three prostate cancer cell lines (PC3, DU145, and LNCaP) were treated with enhydrin, and its effects were analyzed using cell viability assays, morphological observation, flow cytometry, apoptosis-focused TaqMan qPCR array, qRT-PCR, and Western blotting. In vivo antitumor activity was assessed in a PC3 xenograft mouse model. Enhydrin reduced cell viability in a dose- and time-dependent manner, induced morphological changes associated with cytotoxicity, and caused G1 cell-cycle arrest. Gene expression analysis revealed downregulation of PI3K/AKT- and NF-κB-related genes and modulation of BCL2 family genes toward a pro-apoptotic profile, which was confirmed at both mRNA and protein levels. In vivo, enhydrin suppressed tumor growth without significant body-weight loss. These findings suggest that enhydrin exerts antitumor effects in prostate cancer by reducing the expression of PI3K/AKT and NF-κB related molecules and modulating apoptosis-related proteins. Although additional studies are required to determine pathway activity, directly confirm apoptosis, and evaluate normal-cell cytotoxicity and the therapeutic window, these findings provide preliminary biological evidence of the effects of enhydrin in prostate cancer models. Full article

Macrophages are highly plastic innate immune cells that integrate diverse microenvironmental cues to adopt pro-inflammatory (M1) or anti-inflammatory (M2) functional states, which critically influence the pathogenesis of infectious, autoimmune, inflammatory, and malignant diseases. This review provides an overview of current concepts of macrophage ontogeny, functional heterogeneity, and disease-associated phenotypes, with a specific focus on experimental approaches used as M1/M2 test systems for macrophage phenotyping. The scope of the review encompasses commonly used experimental models, induction protocols for M1- and M2-like polarization, and key readouts, including gene-expression signatures and metabolic parameters. Particular emphasis is placed on reporter-based platforms (luciferase, BRET, fluorescent nanoparticle probes), label-free biophysical methods such as electrical impedance monitoring and metabolic profiling, and their application to dynamic, real-time assessment of macrophage phenotype in the context of tumor microenvironments and chemotherapeutic exposure. The potential of integrating reporter systems with single-cell omics, spatial transcriptomics, and patient-derived ex vivo platforms is considered, with a view to transforming M1/M2 test systems into clinically oriented assays capable of tracking macrophage programs during therapy and supporting the development of macrophage-targeted diagnostics and treatments. Full article

Carrageenan is a sulfated polysaccharide extracted from red algae, widely utilized in the food and pharmaceutical industries due to its unique gelling properties and biological activities. However, its high molecular weight and low solubility limit certain high-value applications. Carrageenases specifically degrade carrageenan to produce low-molecular-weight oligosaccharides with excellent bioactivities, thereby overcoming this bottleneck. This review systematically summarizes the microbial sources of carrageenases and the classification characteristics of their three types (κ, ι, and λ) within the GH16, GH82, and GH150 families. Furthermore, it highlights recent advances in molecular engineering strategies, including site-directed mutagenesis and non-catalytic domain fusion, as well as enzyme immobilization techniques utilizing carriers such as magnetic nanoparticles and metal–organic frameworks, which significantly enhance thermostability, catalytic efficiency, and reusability. Additionally, the potential applications of carrageenan oligosaccharides in biomedical fields, including antioxidant, immunomodulatory, antitumor, and anti-inflammatory activities, are thoroughly discussed. This review provides a theoretical reference for the rational design and industrial application of carrageenases, while also offering new insights for the high-value development of algal resources. Full article

Drug-mediated intravesical therapy is a widely used treatment approach for bladder cancer (BCa), which is limited by poor tumor accumulation and the toxicity of drugs. Herein, a facile approach utilizing magnetic hyperthermia therapy (MHT) for BCa treatment is reported through intravesical instillation of tumor-targeting iron oxide nanoparticles (IONPs), which are coated with anti-FGFR3 antibodies for specific binding to FGFR3 overexpressed on BCa cells. The antibody coating significantly enhanced targeting ability and increased cancer cell uptake. Under an alternating magnetic field (AMF), the IONPs magnetothermally activated TRPV1 on the endoplasmic reticulum (ER) of BCa and induced Ca²⁺ overload in RT4 BCa cells. The magnetothermal treatment significantly upregulated the pro-apoptotic gene expression of Bax, Pro-caspase-3, and Cytc in RT4 cells, and downregulated the anti-apoptotic effector gene Bcl-2, ultimately causing augmented apoptosis in cancer cells. The application of intravesical FGFR3-targeting MHT successfully resulted in greater suppression of tumor growth and improved survival rate of mice, compared to the control, IONP, and AMF-treated groups. These results hold significant potential as a transformative modality toward BCa therapeutic application. Full article

Breast cancer is a highly heterogeneous malignancy that remains one of the leading causes of cancer-related mortality among women worldwide. Despite significant advances in breast cancer research and therapy, disease heterogeneity, treatment resistance, and metastatic progression remain major obstacles to effective disease management. Among the molecular regulators involved in breast cancer, microRNAs (miRNAs) have been recognized as critical post-transcriptional regulators of gene expression, functioning as either oncogenes or tumor suppressors. By modulating the expression of target RNAs, miRNAs control key biological processes involved in tumor initiation and progression, including cell proliferation, apoptosis, angiogenesis, epithelial–mesenchymal transition (EMT), invasion, and metastasis. To investigate miRNA function and explore their therapeutic potential, a wide range of approaches have been developed to modulate miRNA expression. These include gain-of-function strategies, like miRNA mimics, miRNA expression vectors, and CRISPR activation (CRISPRa), as well as loss-of-function approaches, including anti-miRNA oligonucleotides (AMOs), miRNA sponges, CRISPR-Cas9-mediated gene knockout, and CRISPR interference (CRISPRi). This review provides a comprehensive overview of the biological roles of miRNAs in breast cancer and discusses current technologies for miRNA modulation, their molecular mechanisms, experimental and therapeutic applications, and associated limitations. In addition, it summarizes recent advances in miRNA delivery systems, including viral vectors, organic nanoparticles, and inorganic nanocarriers, highlighting their potential to improve delivery efficiency, target specificity, and facilitate clinical translation. Finally, the review discusses future perspectives, emphasizing the transition from single-target interventions toward network-level regulation and the integration of miRNA-based strategies into precision oncology to support the development of more effective breast cancer therapies. Full article

A standardized extract of cultured Lentinula edodes mycelia (ECLM), commercially known as AHCC^®, shows anti-inflammatory, immunomodulatory, and organ-protective properties. Experimental studies have indicated that ECLM modulates innate and adaptive immunity, including natural killer (NK) cell activity, antigen-presenting cell function, T-cell responses, and cytokine balance. These effects are particularly relevant in oncology because surgical stress and ischemia–reperfusion injury (IRI) generate a transient perioperative environment characterized by immune suppression, inflammation, and conditions favorable for metastatic progression. Recent animal studies have demonstrated the protective effects of ECLM in intestinal and hepatic IRI models, providing a potential mechanistic rationale for improving the perioperative host microenvironment. Clinical studies on hepatocellular carcinoma, pancreatic cancer, and gynecological malignancies suggest that ECLM may offer potential benefits in immune preservation, nutritional support, symptom management, and recurrence prevention, although most studies are small and hypothesis-generating. Emerging evidence from patient-derived xenograft and spontaneous carcinogenesis models further suggests that ECLM may influence tumor biology beyond host immune activation, although the underlying mechanisms require elucidation. This review summarizes the mechanistic, preclinical, translational, and clinical evidence supporting the use of ECLM as a candidate for perioperative immunonutritional strategies. We propose the hypothesis that ECLM may function as a perioperative microenvironmental stabilizer that integrates immune preservation and intestinal barrier protection. Full article

Extracellular vesicles (EVs) are crucial mediators of intercellular communication in the tumor microenvironment (TME) which facilitate the transfer of bioactive molecules including functional mitochondria and their integral components. This review summarizes the emerging role of EV-mediated mitochondrial transfer in cancer progression. We delineate the mechanisms governing the packaging of mitochondria and their constituents into EVs and subsequently highlight their multifaceted functions across various malignancies, including breast cancer, prostate cancer, blood malignancies, head and neck squamous cell carcinoma, digestive system cancers, etc. Mitochondrial cargo, such as intact mitochondria, mitochondrial DNA (mtDNA), and RNA (mtRNA), are shown to reconfigure metabolism, enhance bioenergetics, promote proliferation and invasion, induce drug resistance, and remodel TME by suppressing antitumor immunity. While previous reviews have predominantly focused on the role of mitochondrial transfer in individual cancers or specific systemic diseases, we made a comprehensive overview encompassing diverse cancer types. These findings suggest that EV-mediated mitochondrial cargo transfer represents a biological intercellular communication mechanism with implications for tumor progression and therapeutic resistance. It is worth noting that we also apply standardized evidence-grading frameworks (C1–C4) across cancer types to provide a critical assessment of the current evidence and identify key methodological gaps that must be addressed in future studies. Collectively, this review underscores the significance of EV-mediated mitochondrial transfer as an important biological process in cancer, presenting it as a promising frontier for novel diagnostic and therapeutic interventions. Full article

Microbial melanins are natural pigments with broad application potential, and Aureobasidium melanogenum is a promising strain for industrial production of melanin. However, the separation, purification, and biological activities of melanin derived from this strain remain largely unexplored. In this study, an efficient extraction and purification process for melanin from the fermentation broth of A. melanogenum GXZ-6 was established through single-factor optimization, and the final purity of the melanin reached 94.4%. Spectroscopic stability tests showed that the melanin was highly stable under dark, natural light, a wide pH range (2–12), and temperatures ≤ 37 °C. However, UV light, high temperature (>50 °C), ultrasonication, and certain metal ions (especially Cr³⁺) markedly altered its absorbance at 225 nm. More importantly, the purified melanin exhibited concentration-dependent antiproliferative activity against human cancer cell lines of A549, HCT116, MCF-7, and HepG2, with IC₅₀ values ranging from 25.50 to 72.33 μg/mL. HepG2 cells were the most sensitive (IC₅₀ = 25.50 μg/mL), and the melanin showed moderate selectivity toward normal hepatocytes (LO2). Mechanistic studies revealed that melanin effectively inhibited HepG2 cell migration, induced apoptosis, depolarized the mitochondrial membrane potential, and activated the caspase-3/PARP pathway. In summary, this study provides a simple, scalable, and environmentally friendly process for producing high-purity melanin with potential antitumor activity. Full article

Caseinolytic protease P (ClpP) is essential for maintaining mitochondrial protein homeostasis, and its activation has emerged as an attractive cancer therapeutic strategy. However, ONC201 is currently the only approved ClpP activator, and its low potency leads to high clinical doses, driving an urgent demand for highly potent agents. In this study, utilizing a ring-opening-based molecular simplification strategy, we identified a class of activators based on a novel piperidine-fused imidazolone scaffold. Through side-chain optimization, we ultimately obtained CLPP-3036 as a highly potent compound. CLPP-3036 exhibits nanomolar enzymatic potency (EC₅₀ = 6.02 nM, 146-fold more potent than ONC201) and excellent antiproliferative activity (MV4-11 IC₅₀ = 1.13 nM). Importantly, CLPP-3036 demonstrates significantly superior inhibitory activity compared to ONC201 across multiple hematologic and solid tumor cell lines, such as Raji cells (IC₅₀ = 9.8 nM, nearly 1260-fold more potent). Furthermore, CLPP-3036 promotes the degradation of ClpP substrate proteins and effectively triggers apoptosis in MV4-11 cells. Collectively, CLPP-3036 is a potent piperidine-fused imidazolone ClpP activator and represents a promising lead compound worthy of further study. Full article