Search Results (3,778)

This study focuses on the isolation, characterization, and evaluation of cytotoxicity of triterpenes extracted from argan pulp. The unsaponifiable lipids extracted from argan pulp are separated into five fractions, two of which are triterpene fractions F2 (composed of α-amyrin, β-amyrin, lupeol, ψ-taraxasterol, taraxasterol) and F4 (erythrodiol). The extraction process utilized solvent-based methods followed by purification through column chromatography. Structural elucidation was carried out using GC-MS and NMR techniques. The cytotoxic activity of the fractions was evaluated against HepG2, MCF-7, and HeLa cell lines. Fraction F4 exhibited IC₅₀ values of 45.58, 71.24, and 98.80 µg/mL, respectively, while fraction F2 showed IC₅₀ values of 122.6, 167.8, and 212.7 µg/mL. Annexin V–FITC/PI flow-cytometry analysis was performed on HepG2 cancer cells and THLE-2 non-tumor cells treated with F4. The results showed a concentration-dependent increase in apoptosis in HepG2 cells, with minimal necrosis. To complement the experimental results, computational analyses were performed to evaluate the pharmacokinetic properties. The triterpenes showed favorable drug-like characteristics and low predicted toxicity. Molecular docking revealed strong interactions with key cancer-related targets, including BCL-2, estrogen receptor α, and HPV16 E6. Full article

Soluble variants of recombinant T cell receptors (TCRs) have become attractive tools for the retargeting of cytotoxic T cells toward intracellular tumor or viral antigens by combining them with CD3-binding antibodies in bispecific T cell engagers; however, TCR-based NK cell engagers have not been studied so far. Here, we developed TCR-based bispecific agents for the redirection of NK cells utilizing a bivalent IgG1-like format. Trifunctional NK engagers included an Fc part with enhanced binding to FcγRIII/CD16A and single-chain (scFv) antibodies recognizing either NKp46 or CD16A, activating NK cell receptors. HCMV pp65/HLA-A2 reactive TCR-scFv-Fc fusion proteins incorporating an affinity-matured TCR and anti-NKp46 scFv activated peripheral blood NK cells and induced cytotoxicity in an antigen-specific manner. For T cell redirection, TCR-scFv-Fc fusion proteins included an scFv antibody recognizing CD3ε. Compared with NK cell engagers, T cell engagers showed similar sensitivity but lower peptide selectivity. For two TCRs recognizing melanoma-associated peptides, affinity-matured TCR-scFv-Fc fusion proteins enabled NK and T cell redirection and activation, and killing of tumor target cells loaded with exogenous peptides. Our results expand the versatility of the soluble TCR technology to NK cell engagers; however, they still require improvement in sensitivity to target tumor cells with low peptide/MHC-I complex densities. Full article

The efficacy of adoptive cell transfer (ACT) therapy in solid tumors is often limited by the functional exhaustion and insufficient persistence of infused CD8⁺ T cells within the tumor microenvironment. Through the integrated analysis of single-cell transcriptomic data, this study identified enolase 1 (ENO1), a key rate-limiting enzyme in glycolysis, as a core gene highly correlated with the superior anti-tumor phenotype of tumor-infiltrating lymphocytes (TILs). However, in vitro functional validation demonstrated that the overexpression of Eno1 failed to substantially enhance the anti-tumor efficacy of mouse T cells, suggesting the presence of a downstream metabolic regulatory node within the glycolytic cascade that restricts the conversion of carbon flux. To overcome this limitation, we introduced the small molecule activator TEPP-46 to target a crucial downstream metabolic hub, pyruvate kinase M2 (PKM2). Transcriptome sequencing confirmed that PKM2 activation successfully induced systemic metabolic rewiring in CD8⁺ T cells and broadly upregulated the expression of cytotoxicity- and memory-related genes. In an in vivo B16-OVA melanoma model, OT-1 T cells subjected to In vitro TEPP-46 pretreatment exhibited significantly enhanced tumor-suppressive capabilities and effectively promoted the preferential differentiation of T cells into central memory T cells (Tcm). In summary, this study highlights the importance of targeting downstream metabolic nodes to bypass intrinsic metabolic restrictions in T cells. It demonstrates that in vitro metabolic pretreatment via PKM2 activation represents an effective translational strategy for optimizing the anti-tumor efficacy of ACT cell products. Full article

Lung cancer is currently the most frequently diagnosed malignancy worldwide, accounting for approximately 12.4% of all cancers and, despite major advances in molecularly targeted therapies and immunotherapy, represents the leading cause of cancer-related mortality. In recent years, antibody–drug conjugates (ADCs) have emerged as a novel therapeutic strategy, combining the specificity of monoclonal antibodies with the potent cytotoxic activity of highly active payloads to selectively target tumor cells while limiting systemic toxicity. This narrative review summarizes the current role of ADCs in lung cancer, with particular focus on their structural components, mechanisms of action, and the biological features that determine treatment efficacy. We discuss the rationale for targeting established and emerging antigens in non-small cell and small cell lung cancer, including HER2, TROP2, c-MET, HER3, CEACAM5, DLL3, and other promising targets currently under clinical investigation. The principal mechanisms of primary and acquired resistance are also reviewed, including antigen modulation, altered intracellular trafficking, lysosomal dysfunction, drug efflux, tumor microenvironment-mediated immune suppression, and intratumor heterogeneity. In addition, we provide an overview of the safety profile of ADCs, highlighting the most clinically relevant adverse events and their underlying biological mechanisms. We also examine the evolving landscape of predictive biomarkers beyond antigen expression, including genomic, transcriptomic, proteomic, and liquid biopsy-based approaches, together with emerging spatial and single-cell technologies that may improve patient selection. Finally, we discuss future directions in the field, including novel payloads, next-generation linker technologies, bispecific ADCs, combination strategies, and personalized ADC development. Overall, ADCs are rapidly reshaping the therapeutic landscape of lung cancer. Continued optimization of drug design, biomarker-driven patient selection, and a deeper understanding of resistance mechanisms will be essential to fully realize their clinical potential. Full article

Carbohydrates and their constituent monosaccharides have historically been viewed as metabolic substrates that provide cellular energy. However, recent evidence demonstrates that monosaccharides can also function as bioactive signaling molecules that affect immune responses through cellular metabolic reprogramming, post-translational protein glycosylation, receptor complex modulation, and transcriptional regulation of immune cell differentiation. These discoveries have given rise to the emerging concept of glyconutraceuticals, bioactive carbohydrates with therapeutic potential. This review discusses current evidence for the immunomodulatory properties of glucose, D-mannose, sialic acid, L-fucose, galactose, N-acetylglucosamine, D-xylose, and L/D-arabinose, with particular emphasis on their mechanisms of action in T cell activation, subset differentiation, metabolic reprogramming, and anti-tumor cytotoxicity. The context-dependent and often opposing effects of individual monosaccharides across T cell subsets underscore the complexity of immunomodulation by glyconutrients. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) is the most prevalent primary liver tumor and is often diagnosed at advanced stages with very poor therapeutic response, leading to high mortality. Thus, new therapeutic strategies and biomarkers are urgently needed. We previously showed that the combination of loratadine, raloxifene, and sorafenib exerts synergistic cytotoxicity on HCC cells. Here, we explored potential molecular mechanisms underlying the anticancer effects of this combination using multiomics analyses. Methods: We performed proteomic analyses based on mass spectrometry, transcriptomic analyses using the Clariom D Plus human microarray (Affymetrix), and metabolomic analyses based on nuclear magnetic resonance to investigate the profile changes induced by the drug combination in HuH7 cells. Bioinformatic analyses were applied to associate the omics changes with biological functions, molecular interactions, and clinical relevance in terms of patient survival. Results: We identified several molecules whose expression changed in response to treatment across the three omics profiles analyzed. Some of them were found to be involved in hallmarks of cancer, including sustained proliferation, evasion of growth suppressors, and resistance to cell death. Integrated multi-omics analyses revealed that the drug combination suppresses critical oncogenic drivers (C7orf50, NUP188, and HS2ST1) and that the mitotic cell cycle process, DNA synthesis and cholesterol biosynthesis are the primary pathways affected. Protein–protein interaction analysis revealed five key hubs (KIF2C, PCNA, TRIP13, NDC80, and RPA3), whose expression in HCC is associated with poor clinical prognosis. Conclusions: The combined treatment rewired molecular networks involved in HCC progression. These findings identify clinically relevant molecular targets associated with poor prognosis and provide mechanistic insights into the synergistic anticancer activity of this drug combination. Full article

Anti-CD226 antibody-mediated stimulation of NK-92 cells (sNK-92) represents a potential immunotherapeutic approach; however, its cytotoxic and apoptosis-associated effects in hormone-independent solid tumors remain insufficiently characterized. This study investigated the activity of sNK-92 cells against PC3 castration-resistant prostate cancer and SH-SY5Y neuroblastoma cell lines, using PNT1A normal prostate epithelial and BJ normal dermal fibroblast cells as non-malignant controls. Cytotoxicity was assessed by CCK-8 assay at target-to-effector (T:E) ratios of 1:1, 1:5, and 1:10, and markers historically associated with the intrinsic (BAX, caspase-9), extrinsic (caspase-8), and executioner (caspase-3) apoptotic pathways were evaluated quantitatively by ImageJ-based corrected total cell fluorescence (CTCF) analysis. sNK-92 cells produced significant ratio-dependent cytotoxicity against PC3 and SH-SY5Y cells, reaching 23.76% and 26.29%, respectively, at the 1:10 T:E ratio, with sNK-92 producing significantly greater cytotoxicity than unstimulated NK-92 at this ratio in both cell lines and additionally at the 1:5 ratio in SH-SY5Y cells; no significant reduction in CCK-8 viability was detected in PNT1A or BJ cells at any ratio. Quantitative immunofluorescence analysis demonstrated substantially increased relative fluorescence intensity of all four apoptosis-associated markers in sNK-92-treated PC3 and SH-SY5Y cells compared with their corresponding controls and, in most comparisons, with NK-92-treated cells, whereas changes observed in the PNT1A and BJ non-malignant models examined were markedly smaller. These findings provide preliminary quantitative evidence that anti-CD226-stimulated NK-92 cells exert a preferential cytotoxic effect on the tumor cell models examined, relative to the non-malignant models tested, and induce changes in apoptosis-associated markers consistent with engagement of apoptotic signaling. Further orthogonal validation is warranted. Full article

To explore the emerging role of natural ligands, specifically coumarin and curcumin, and their coordination with the transition metals ruthenium (Ru) and iridium (Ir) as photosensitizers (PSs) in photodynamic therapy (PDT) for cancer. This highlights the integration of natural compounds and transition metals to overcome limitations in photophysical properties, hypoxia tolerance, and clinical translation. Regarding PDT oncology, this examines an immunological effect on Ru/Ir complexes and natural ligand-metal hybrids. They induce immunogenic cell death (ICD) through reactive oxygen species (ROS) generation, calreticulin exposure, extracellular ATP release, and HMGB1 secretion. These damage-associated molecular patterns act as “danger signals” to recruit dendritic cells, prime CD8⁺ cytotoxic T-cells, and establish systemic antitumor immunity. This study compares natural ligand-metal complexes with conventional Ru(II)/Ir(III) complexes and clinical PSs to assess their translational potential as immune-activating agents in PDT oncology, as well as focusing on the integration of nanotechnology with natural ligand-metal complexes to enhance delivery, biocompatibility, and clinical translation. A narrative review was conducted of the literature published between 2010 and 2025 across multiple electronic databases, including WanFang Data, PubMed, ScienceDirect, Scopus, Web of Science, Springer Link, SciFinder, and CNKI, without language restrictions. Studies focusing on coumarin, curcumin, Ru(II), Ir(III), and PDT were analyzed. Extracted data included chemical structures, absorption and emission spectra, singlet oxygen yields, biological activities, and therapeutic outcomes. Comparative evaluation was performed between free natural ligands, their Ru(II)/Ir(III) complexes, and nanodelivery systems to assess efficacy, biocompatibility, and translational potential. Coumarin and curcumin exhibited intrinsic antioxidant, anti-inflammatory, and anticancer properties but were limited by short absorption/emission ranges, poor photostability, and low singlet oxygen yields, restricting preclinical application. Coordination with Ru(II) and Ir(III) significantly enhanced intersystem crossing, extended absorption into the near-infrared region, and improved singlet oxygen quantum yields (Φ_Δ up to ~0.78). These complexes demonstrated potent photocytotoxicity under normoxia and hypoxia, achieving IC₅₀ values in the nanomolar range, which indicated organelle-specific targeting (mitochondria, lysosomes, ER), induced ICD, and synergized with checkpoint blockade. Nanocarrier encapsulation further improved solubility and tumor selectivity, and reduced systemic toxicity. Coumarin- and curcumin-based Ru/Ir complexes represent promising next-generation or immune activating PDT agents by combining natural pharmacological activity with superior photophysical performance. The ability to generate reactive oxygen species under hypoxia and achieve multimodal therapeutic effects positions them as strong candidates for clinical translation. Clinical approval of natural ligand-Ru/Ir complexes depends on rigorous safety, pharmacokinetic, and nanodelivery validation, but these complexes clearly extend PDT beyond local cytotoxicity toward durable immune protection. Future research should prioritize ligand engineering, nanotechnology integration, and translational models to bridge preclinical promise with safe and effective clinical applications. Full article

Photodynamic therapy (PDT) is a minimally invasive anticancer modality based on the interaction of a photosensitizer, light of an appropriate wavelength, and molecular oxygen, resulting in reactive oxygen species (ROS)-mediated tumor injury. This review discusses PDT as a mechanism-dependent therapeutic platform and evaluates how photosensitizers, vitamin A, vitamin D, nanotechnology, and combination strategies may influence its efficacy. The article synthesizes mechanistic and translational evidence concerning photosensitizer activation, ROS generation, tumor cell death, vascular shutdown, immunogenic cell death, and clinically relevant PDT applications. Particular attention is given to the divergent roles of vitamin A and vitamin D. Mechanistic and limited experimental evidence indicates that the effects of vitamin A-related compounds on PDT are heterogeneous and context-dependent. Selected compounds may attenuate PDT through antioxidant or cytoprotective mechanisms, whereas enhancement has also been reported for specific retinoid–photosensitizer combinations; however, clinical evidence remains limited. In contrast, vitamin D may enhance ALA/MAL-PDT by increasing intracellular protoporphyrin IX accumulation through modulation of the heme biosynthetic pathway, especially in non-melanoma skin cancer contexts. Nanocarriers, targeted photosensitizers, oxygen-modulating platforms, chemotherapy, and immunotherapy may further improve PDT when selected according to mechanistic compatibility. Overall, PDT combination design should be guided by whether adjunctive agents support or undermine photosensitizer accumulation, oxygen availability, ROS-mediated cytotoxicity, and immune activation. Full article

Background: The immune landscape in head and neck squamous cell carcinoma (HNSCC) has been widely investigated. However, the crucial role played by the lymph node microenvironment in metastatic and non-metastatic HNSCC remains unknown. This systematic review aims to discuss the immunological crosstalk between the tumor and the nodal microenvironment and to describe the distribution of immune cells in metastatic and non-metastatic lymph nodes. Methods: A systematic review was conducted according to the PRISMA guidelines. PubMed, Scopus, and the Cochrane Library were searched for studies published between 1990 and 2025, with the final search performed in December 2025. Prospective and retrospective studies evaluating immune cell infiltration in metastatic and non-metastatic cervical lymph nodes were included, whereas studies focusing exclusively on non-cellular biomarkers and non-English publications were excluded. The risk of bias was assessed using the Newcastle–Ottawa Scale. The results were synthesized narratively, and no meta-analysis was performed. Results: The screening process identified 608 articles, of which 27 met our predefined inclusion criteria. These studies focused on macrophages, dendritic cells, neutrophils, natural killer cells, T helper cells, cytotoxic T cells, regulatory T cells, B cells, total lymphocytes, and surface markers. This systematic review provides a well-structured analysis of current knowledge on the impact of the innate and adaptive immune systems on the response against cancer cells and the recruitment of immune cells in lymph nodes. The most significant findings highlight the crucial role of antigen presentation in the antitumor response, particularly through the recruitment and activation of dendritic cells and subcapsular sinus macrophages in tumor-draining lymph nodes. It also presents in a fairly comprehensible manner that the density of mature dendritic cells, cytotoxic T cells, and B cells is higher in non-metastatic lymph nodes. Discussion: The lymph node microenvironment is highly enriched with immune cell infiltration, and their distribution between metastatic and non-metastatic lymph nodes can contribute to a better understanding of the underlying pathological processes. Particular attention should be given to the innate immune system cells and their implication in antigen presentation. Our findings suggest that identifying immunological profiles of lymph nodes may provide a rationale for treatment de-escalation protocols and raise the question of lymph node preservation in antitumor immune responses. However, the heterogeneity and bias assessment of the included studies warrant a cautious interpretation of these findings. Another important limitation is the limited number of studies comparing the immune microenvironment of primary tumors and lymph nodes. Full article

Chlorogenic acid (CGA) exhibits anticancer activity in colorectal cancer (CRC), but its clinical application is limited by low lipophilicity. To improve its physicochemical properties, four CGA esters (methyl, ethyl, n-propyl, and n-butyl chlorogenates) were synthesized and evaluated. Physicochemical properties were characterized in silico, and their biological activity was assessed in SW480, HT-29, and non-tumoral NCM460 cell lines using viability assays and flow cytometry. Molecular docking studies were performed to investigate the interactions of CGA and its esters with proteins involved in cell-proliferation-related signaling pathways. In silico analysis showed a progressive increase in LogP values across ester derivatives. All esters complied with Lipinski’s rule of five, whereas none met Veber’s rule due to their predicted topological polar surface area (TPSA) values. The esters induced dose- and time-dependent reductions in cell viability, with n-butyl chlorogenate exhibiting the strongest cytotoxic activity and a significantly lower IC₅₀ value within the tested concentration range. This derivative showed preferential cytotoxic activity toward SW480 cells while exhibiting only limited effects in non-tumoral NCM460 cells. In addition, n-butyl chlorogenate induced changes in mitochondrial oxidative status and phosphatidylserine externalization, consistent with apoptosis-associated cellular changes. Overall, these findings demonstrate that esterification modifies the physicochemical profile of CGA ester derivatives and is associated with enhanced cytotoxic activity. Increased lipophilicity was associated with enhanced cytotoxic activity, supporting further optimization of these compounds for CRC research. Full article

Background: Lung cancer remains the leading cause of cancer-related mortality worldwide, with five-year survival below 5% for metastatic small cell lung cancer (SCLC) and below 10% for metastatic non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors have improved outcomes, but primary and acquired resistance, driven by tumor microenvironment immunosuppression, antigen heterogeneity, and T-cell exhaustion, leaves a substantial unmet need. T-cell engagers (TCEs), bispecific antibodies that redirect cytotoxic T-cells to tumor cells independent of MHC-I-restricted antigen presentation, offer a mechanistically distinct approach. Methods: We conducted a structured narrative review, without formal PRISMA methodology or meta-analytic pooling, of PubMed, Embase, and ClinicalTrials.gov through June 2026, supplemented by conference abstracts from ASCO, ESMO, AACR, and ATS, covering clinical, translational, and preclinical evidence for TCEs across established and emerging targets in thoracic malignancy. Results: Tarlatamab, a DLL3/CD3 bispecific TCE, received full FDA approval in November 2025 based on DeLLphi-304 data showing a median overall survival benefit of 13.6 versus 8.3 months over chemotherapy (HR 0.60; p < 0.001), establishing proof-of-concept for the TCE platform in lung cancer and NCCN Category 1 status in ES-SCLC. Beyond DLL3, an expanding pipeline of targets, including Claudin-18.2, TROP-2, FOLR1, CD70, and HER2, is under active TCE development; several of these antigens have independently validated tumor-selective expression through approved or late-stage antibody-drug conjugates (ADCs), providing target-level clinical de-risking for TCE development, though the two modalities have distinct requirements for antigen density and internalization that must be independently validated. Novel tri-specific constructs incorporating costimulatory domains and combination strategies with checkpoint inhibitors are in early clinical development. Conclusions: Tarlatamab approval validates the TCE platform in lung cancer, but overcoming TME-mediated resistance, antigen heterogeneity, and class-specific toxicities including cytokine release syndrome remains the central challenge. Rational TCE design, incorporating costimulatory signaling, antigen selection informed by parallel ADC validation data, and evidence-based combination strategies, offers the most credible path toward expanding this platform’s impact in metastatic lung cancer. 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

Background: Paclitaxel is a cornerstone chemotherapeutic agent widely used in breast cancer treatment, primarily through the stabilization of microtubule dynamics. Beyond its canonical tubulin-targeting activity, increasing evidence suggests that paclitaxel may engage additional molecular targets, contributing to its complex pharmacological profile. In this study, an integrated computational workflow was applied to evaluate the structural compatibility between paclitaxel and the neurokinin-2 receptor (NK2R), a G protein-coupled receptor involved in tumor-associated inflammatory and proliferative signaling pathways. Physicochemical profiling and target prediction were performed using SwissADME and SwissTargetPrediction, followed by molecular docking and molecular dynamics simulations using AutoDock Vina and GROMACS 2024.1. Paclitaxel exhibited physicochemical properties consistent with transient interactions in hydrophobic transmembrane environments. Docking analysis identified a plausible binding mode within the NK2R transmembrane cavity, primarily stabilized by hydrophobic contacts. Molecular dynamics simulations over 100 ns revealed stable ligand occupancy and overall complex stability, while MM-PBSA calculations indicated a favorable transient association. The predicted interaction is consistent with secondary or non-canonical receptor engagement. While NK2R is not established as a pharmacological target of paclitaxel, the results support the structural feasibility of a previously uncharacterized receptor interaction and provide a reproducible computational framework for exploring GPCR-associated effects of cytotoxic agents. 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