Search Results (171)

Cancer remains a significant global health burden despite advances in diagnosis and treatment. In recent years, drug repurposing has emerged as a promising strategy in oncology, offering reduced costs and shorter development timelines compared with de novo drug discovery. Among repurposed agents, the antifungal drug itraconazole has demonstrated anticancer activity across multiple tumor types, particularly when used in combination with other therapeutic modalities. In this review, we summarize current preclinical and clinical evidence supporting the use of itraconazole in cancer therapy, with a specific focus on its combination with chemotherapeutic agents and programmed cell death protein 1 (PD-1) immune checkpoint inhibitors. We highlight proposed mechanisms underlying this synergy, including modulation of tumor metabolism, angiogenesis, and immune signaling pathways. Additionally, we discuss key challenges and limitations, such as drug–drug interactions and toxicity considerations, that must be addressed to optimize clinical translation. Overall, the combination of itraconazole with chemotherapy or anti-PD-1 therapy represents a promising therapeutic strategy warranting further investigation in well-designed trials. Full article

Metastasis is still the leading cause of cancer-related death. It happens when disseminated tumor cells (DTCs) successfully navigate a series of steps and adapt to the unique conditions of distant organs. In this review, key molecular and immune mechanisms that shape metastatic spread, long-term survival, and eventual outgrowth are examined, with a focus on how tumor-intrinsic programs interact with extracellular matrix (ECM) remodeling, angiogenesis, and immune regulation. Gene networks that sustain tumor-cell plasticity and invasion are described, including EMT-linked transcription factors such as SNAIL and TWIST, as well as broader transcriptional regulators like SP1. Also, how epigenetic mechanisms, such as EZH2 activity, DNA methylation, chromatin remodeling, and noncoding RNAs, lock in pro-metastatic states and support adaptation under therapeutic pressure. Finally, proteases and matrix-modifying enzymes that physically and biochemically reshape tissues, including MMPs, uPA, cathepsins, LOX/LOXL2, and heparinase, are discussed for their roles in releasing stored growth signals and building permissive niches that enable seeding and colonization. In parallel, immune-evasion strategies that protect circulating and newly seeded tumor cells are discussed, including platelet-mediated shielding, suppressive myeloid populations, checkpoint signaling, and stromal barriers that exclude effector lymphocytes. A major focus is metastatic dormancy, cellular, angiogenic, and immune-mediated, framed as a reversible survival state regulated by stress signaling, adhesion cues, metabolic rewiring, and niche constraints, and as a key determinant of late relapse. Tumor-specific metastatic programs across mesenchymal malignancies (osteosarcoma, chondrosarcoma, and liposarcoma) and selected high-burden cancers (melanoma, hepatocellular carcinoma, glioblastoma, and breast cancer) are highlighted, emphasizing shared principles and divergent organotropisms. Emerging therapeutic strategies that target both the “seed” and the “soil” are also discussed, including immunotherapy combinations, stromal/ECM normalization, chemokine-axis inhibition, epigenetic reprogramming, and liquid-biopsy-enabled minimal residual disease monitoring, to prevent reactivation and improve durable control of metastatic disease. Full article

Pseudouridine (Ψ), the most abundant RNA modification, plays essential roles in shaping RNA structure, stability, and translational output. Beyond cancer, Ψ is dynamically regulated across numerous physiological and pathological contexts—including immune activation, metabolic disorders, stress responses, and pregnancy-related conditions such as preeclampsia—where elevated Ψ levels reflect intensified RNA turnover and modification activity. These broad functional roles highlight pseudouridylation as a central regulator of cellular homeostasis. Emerging evidence demonstrates that Ψ dysregulation contributes directly to the development and progression of several women’s cancers, including breast, ovarian, endometrial, and cervical malignancies. Elevated Ψ levels in tissues, blood, and urine correlate with tumor burden, metastatic potential, and therapeutic responsiveness. Aberrant activity of Ψ synthases such as PUS1, PUS7, and the H/ACA ribonucleoprotein component dyskerin alters pseudouridylation patterns across multiple RNA substrates, including rRNA, tRNA, mRNA, lncRNAs, snoRNAs, and ncRNAs. These widespread modifications reshape ribosome function, modify transcript stability and translational efficiency, reprogram RNA–protein interactions, and activate oncogenic signaling programs. Advances in high-resolution, site-specific Ψ mapping technologies have further revealed mechanistic links between pseudouridylation and malignant transformation, highlighting how modification of distinct RNA classes contributes to altered cellular identity and tumor progression. Collectively, Ψ and its modifying enzymes represent promising biomarkers and therapeutic targets across women’s cancers, while also serving as sensitive indicators of diverse non-cancer physiological and disease states. Full article

Background/Objectives: Sex-specific differences in metabolic dysfunction-associated fatty liver disease (MAFLD)-related hepatocellular carcinoma (HCC) remain poorly understood. This study aimed to clarify sex-associated disparities in disease progression and recovery using a diethylnitrosamine (DEN) plus Western diet/fructose-induced murine model combined with artificial intelligence (AI)-assisted histological analysis. Methods: Male and female C57BL/6J mice received a single diethylnitrosamine injection and were fed a Western diet/fructose regimen for 38 weeks, followed by an 8-week recovery period on standard chow. Serum biochemical parameters were measured, and liver histology was assessed using second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) microscopy. Steatosis and fibrosis were quantified within tumor and adjacent non-tumor regions using AI-based image analysis. Results: Male mice developed more severe disease phenotypes, including greater tumor burden and higher serum alanine aminotransferase levels, compared with females. Following dietary recovery, female mice showed substantial reductions in tumor number and hepatic steatosis, particularly in non-tumor regions; in contrast, male mice demonstrated only minimal improvement. AI-assisted quantification confirmed considerable regression of both steatosis and fibrosis in females and moderate fibrosis improvement in both sexes. Conclusions: These findings indicate sexual dimorphism in the progression and regression of MAFLD-related HCC, with females exhibiting enhanced metabolic and histological recovery. The results underscore the importance of considering sex as a biological variable in preclinical metabolic dysfunction–associated fatty liver disease-related hepatocellular carcinoma research and highlight the value of AI-enhanced imaging for precise, objective evaluation of liver histology. Full article

Cervical cancer remains a significant global health burden, with chemoradioresistance representing a major obstacle to successful treatment. To elucidate the mechanisms underlying this resistance, we established a unique pair of isogenic primary cervical cancer cell lines, AdMer35 and AdMer43, obtained from a patient with squamous cell carcinoma of the cervix before and after radiation therapy. The aim of our study was to characterize the transcriptomic and cellular heterogeneity of these cells. We conducted an in-depth comparative analysis using single-cell RNA sequencing. Analysis of this paired, patient-derived isogenic model suggests that chemoradioresistance can arise through coordinated multilevel cellular adaptations. Resistant AdMer43 cells demonstrated transcriptional reprogramming, with the upregulation of embryonic stemness factors (HOX, POU5F1, SOX2), a shift in extracellular matrix from fibrillar to non-fibrillar collagens, and activation of inflammatory pathways. We identified and characterized critical cell-state dynamics: resistant cells exhibited a remodeled ecosystem with a metabolically reprogrammed senescent-like cell population showing an enhanced pro-tumorigenic communication via EREG, SEMA3C, BMP, and WNT pathways. Furthermore, we identified a progenitor-like cell population with a minimal CNV burden, potentially serving as a reservoir for tumor persistence. These findings offer novel insights for developing targeted strategies to eliminate resistant cell pools and improve cervical cancer outcomes. Full article

Background: Lung adenocarcinoma (LUAD) exhibits pronounced cellular and molecular heterogeneity that shapes tumor progression and therapeutic response. Although nucleotide metabolism is essential for sustaining tumor proliferation and coordinating immune interactions, its single-cell heterogeneity and clinical implications remain incompletely defined. Methods: We integrated a publicly available scRNA-seq dataset derived from independent LUAD patients to construct a comprehensive LUAD cellular atlas, identified malignant epithelial cells using inferCNV, and reconstructed differentiation trajectories via Monocle2. Cell–cell communication patterns under distinct nucleotide metabolic states were assessed using CellChat. A nucleotide metabolism-related signature (NMRS) was subsequently developed across TCGA-LUAD and multiple GEO cohorts using 101 combinations of machine learning algorithms. Its prognostic and immunological predictive value was systematically evaluated. The functional relevance of the key gene ENO1 was further verified through pan-cancer analyses and in vitro experiments. Results: We identified substantial nucleotide metabolic heterogeneity within malignant epithelial cells, closely linked to elevated proliferative activity, glycolytic activation, and increased CNV burden. Pseudotime analysis showed that epithelial cells gradually acquire enhanced immune-modulatory and complement-related functions along their differentiation continuum. High-metabolism epithelial cells exhibited stronger outgoing communication—particularly via MIF, CDH5, and MHC-II pathways—highlighting their potential role in shaping an immunosuppressive microenvironment. The NMRS built from metabolism-related genes provided robust prognostic stratification across multiple cohorts and surpassed conventional clinical parameters. Immune profiling revealed that high-NMRS tumors displayed increased T-cell dysfunction, stronger exclusion, higher TIDE scores, and lower IPS, suggesting poorer responses to immune checkpoint blockade. ENO1, markedly upregulated in high-NMRS tumors and functioning as a risk factor in several cancer types, was experimentally shown to promote invasion in LUAD cell lines. Conclusions: This study delineates the profound impact of nucleotide metabolic reprogramming on epithelial cell states, immune ecology, and malignant evolution in LUAD. The NMRS provides a robust predictor of prognosis and immunotherapy response across cohorts, while ENO1 emerges as a pivotal metabolic–immune mediator and promising therapeutic target. Full article

The gut microbiome has emerged as a key regulator of human health, influencing not only metabolism and immunity but also the development and treatment of cancer. Mounting evidence suggests that microbial dysbiosis contributes to oncogenesis by driving chronic inflammation, producing genotoxic metabolites, altering bile acid metabolism, and disrupting epithelial barrier integrity. At the same time, the gut microbiome significantly modulates the host response to oncotherapies including chemotherapy, radiotherapy, and especially immunotherapy, where microbial diversity and specific taxa determine treatment efficacy and toxicity. This review synthesizes current evidence on the role of the gut microbiome in both oncogenesis and oncotherapies, focusing on thirteen cancers with the strongest and most clinically relevant microbiome associations, colorectal cancer, gastric cancer, hepatocellular carcinoma, gallbladder cancer, esophageal cancer, pancreatic cancer, oral squamous cell carcinoma, cervical cancer, prostate cancer, breast cancer, lung cancer, brain cancer, and melanoma. These cancers were selected based on robust mechanistic data linking microbial alterations to tumor initiation, progression, and therapy modulation, as well as their global health burden and translational potential. In addition, we have provided mechanistic insights or clinical correlations between the microbiome and cancer outcomes. Across cancers, common microbial mechanisms included pro-inflammatory signaling (e.g., NF-κB and STAT3 pathways), DNA damage from bacterial toxins (e.g., colibactin, nitrosating species), and metabolite-driven tumor promotion (e.g., secondary bile acids, trimethylamine N-oxide). Conversely, beneficial commensals such as Faecalibacterium prausnitzii and Akkermansia muciniphila supported antitumor immunity and improved responses to immune checkpoint inhibitors. In conclusion, the gut microbiome functions as both a driver of malignancy and a modifiable determinant of therapeutic success. Integrating microbiome profiling and modulation strategies such as dietary interventions, probiotics, and fecal microbiota transplantation into oncology practice may pave the way for personalized and more effective cancer care. Full article

Temozolomide (TMZ) remains foundational in the management of adult-type diffuse gliomas in general, and glioblastoma specifically. However, its efficacy harbors an evolutionary trade-off. TMZ drives its cytotoxicity through generating O⁶-methylguanine lesions, especially active in MGMT-silenced, mismatch repair (MMR)-proficient tumors. By selecting for acquired MMR-deficient subclones, often via MSH6 inactivation, this process escalates into a hypermutator phenotype, generating thousands of de novo alterations. This is a hallmark of the mutational signature known as SBS11, characterized by C>T transitions, which is associated with TMZ treatment. The hypermutator phenotype drives heterogeneity, therapeutic resistance, spatial diversification, and distant recurrence. Despite harboring a mutational burden comparable to melanoma and lung cancer, TMZ-induced hypermutation does not sensitize gliomas to immune checkpoint blockade. This resistance reflects the profoundly immunosuppressive brain microenvironment, impaired antigen presentation, marked transcriptional plasticity, and perhaps also the frequent use of corticosteroids. Emerging strategies aim to exploit vulnerabilities created by TMZ-mediated genomic instability, including PARP, ATR, WEE1, and AURKA inhibition; alternative alkylators; metabolic rewiring; and G-quadruplex stabilization. Notably, the real-time detection of evolving mutational signatures via CSF-based liquid biopsies may enable adaptive therapy before radiographic progression. By reframing TMZ as a potent evolutionary agent rather than a conventional chemotherapy, this review synthesizes recent mechanistic insights and translational opportunities to guide a next-generation, evolution-informed treatment paradigm for glioma. Full article

Human missions into deep space will expose astronauts to the unique and complex radiation environment of galactic cosmic radiation (GCR), a mixed field of high-energy protons and heavy ions predicted to substantially increase long-term cancer risk. To support effective risk stratification, early detection, and mitigation strategies, there is a need to identify biomarkers indicative of GCR-induced cancer risk. Here, we applied a Tandem Mass Tag (TMT)-based quantitative proteomics approach to identify potential biomarkers associated with GCR-induced gastrointestinal (GI) and mammary tumorigenesis using the female Apc^Min/+ mouse, a well-established model of human colorectal and breast cancer. Eight- to ten-week-old Apc^Min/+ mice were exposed to 75 cGy of simulated GCR and serum and tissue samples were collected 100–110 days post-exposure for molecular and histopathological analyses. Tumor incidence was scored by blinded observers, and serum proteomes exhibiting a fold change > 1.2 or <0.83 with p < 0.05 were considered significantly altered. Bioinformatics analyses, including Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway enrichment, and unsupervised clustering, were employed to delineate GCR-responsive molecular networks. Validation of differentially expressed proteins (DEPs) was performed using immunoblotting, ELISA, and enzyme activity assays. GCR exposure resulted in a significant increase in both GI and mammary tumor burden relative to controls. Proteomic profiling revealed 194 upregulated and 461 downregulated proteins, distinguishing GCR-exposed from control serum proteomes. Functional enrichment analyses highlighted alterations in metabolic processes, PI3K-AKT, HIF-1, and PPAR signaling pathways, alongside the suppression of antioxidant defense mechanisms. Notably, mice exposed to GCR exhibited elevated serum levels of TGF-β1 and MMP9, accompanied by reduced levels and enzymatic activities of key antioxidant defenses. Cross-referencing 36 GCR-induced serum SASP factors with the Human Protein Atlas revealed 11 SASP proteins associated with human breast and colorectal cancers. Together, these findings show that GCR exposure triggers a pro-tumorigenic serum proteomic signature that may serve as a biomarker for assessing cancer risk in astronauts during deep-space missions. Full article

Neuroendocrine neoplasms (NENs) are rare and heterogeneous tumors with heterogeneity in morphology and molecular profile and consequently resulting in a heterogeneous biological behavior. They have a more indolent natural history compared to the classic cancer and may emerge in any site of the human body, but usually they have gastroenteropancreatic (GEP) or bronchopulmonary (BP) origin. When NENs are well differentiated, they are called neuroendocrine tumors (NETs) as opposed to poorly differentiated neuroendocrine carcinomas (NECs). They may secrete a bioactive molecule resulting in a secretory syndrome or they may not be associated with any secretory product, defining functional and non-functional NENs. The hormonal hypersecretion syndromes, the chronic symptom burden, the tumor-related inflammation, and the treatment side effects impair nutritional intake and absorption while increasing metabolic needs. The present comprehensive narrative review is summarizing established and emerging methods of nutritional and body composition assessment, and the recent evidence of interventions for sarcopenia and malnutrition in patients with NETs. Early identification and management of malnutrition and sarcopenia are fundamental steps to improve quality of life and clinical outcomes in these patients during the long natural history of these neoplasms. Full article

Hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC) are highly lethal cancers marked by profound epigenetic and metabolic reprogramming. Among the candidate biomarkers, the DNA methyltransferase DNMT3A and the guanine monophosphate synthetase (GMPS) have emerged as potential prognostic drivers, yet their roles across tumor contexts remain unclear. Here, we demonstrate the application of KMplotter to interrogated pan-cancer transcriptomic and survival datasets encompassing over 7000 patients, complemented by expression profiling of normal, tumor, and metastatic tissues, and integrated tumor microenvironment (TME) analyses. Elevated DNMT3A and GMPS expression correlated with worse overall survival in HCC, particularly in Asian patients, while in PDAC, high DNMT3A but low GMPS expression predicted favorable outcomes. Both genes were consistently upregulated in tumors relative to normal tissues, with further increases in metastatic HCC. Immune deconvolution revealed that DNMT3A was linked to Th2/Treg-enriched niches, whereas GMPS overexpression coincided with high mutational burden or stromal enrichment, fostering immunosuppressive microenvironments. Comparative analysis of toll-like receptor signatures highlighted divergent antigen-sensing pathways, with HCC reflecting viral-driven immune exhaustion and PDAC showing self-antigen–associated signaling. Collectively, these findings position DNMT3A and GMPS as context-dependent biomarkers that integrate metabolic and immune cues to shape prognosis in liver and pancreatic cancer, offering mechanistic insight and translational relevance for patient stratification. Full article

Cancer remains a major global health burden driven by genetic, metabolic, and microenvironmental alterations. Although reactive oxygen species (ROS) and oxidative stress have long been implicated in cancer biology, current understanding remains fragmented and, in several areas, conceptually disputed considering how ROS and oxidative stress thresholds determine the switch between tumor-promoting signaling and cytotoxic outcomes, and whether redox-based therapies can be safely and selectively applied across different cancer types. Moreover, existing studies often examine isolated pathways or single ROS, leaving unanswered the question of how spatial and temporal ROS dynamics and oxidative stress responses shape carcinogenesis, metastasis, and therapeutic resistance. This review moves beyond descriptive summarization by critically examining unresolved mechanistic gaps, including (i) how ROS and oxidative stress interact with epigenetic and metabolic reprogramming, (ii) the context-dependent role of ROS-driven oxidative stress within the tumor microenvironment and immune evasion, and (iii) why ROS-targeting and oxidative stress-modulating therapies have shown inconsistent clinical translation despite promising preclinical data. We highlight areas of consensus as well as conflicting evidence, synthesizing recent advances across multiple cancer types to clarify where ROS and oxidative stress function as drivers, modulators, or vulnerabilities. Finally, we outline emerging research priorities, such as real-time redox profiling, subtype-specific targeting strategies, and combination approaches, to guide the development of more precise and effective ROS- and oxidative-stress-based interventions. Full article

Cancer is one of the most feared diseases in the world. Its incidence has increased steadily in recent years; it represents a significant burden of disease and is among the leading causes of death globally. Consequently, the search for novel compounds that serve as potential candidates for pharmacotherapeutic options and that can be used as treatments or adjuvants to control this disease is urgent. In this context, plant-derived phenolic diterpenes have shown antitumor activity against several types of cancer, inhibiting DNA synthesis, lipid metabolism, and bioenergetics of these cells, among other mechanisms, making these compounds an excellent alternative to continue investigating. The objective of this research was to evaluate the action of the previously undescribed natural diterpene 3,3′-diisopropyl-2,2′,5,5′-tetramethoxy-6,6′-dimethylbiphenyl-4,4′-diol (biisoespintanolcompound 2), against several human tumor cell lines (A549, MDA-MB-231, DU145, A2780, A2780-cis) and the non-tumor cell line MRC-5. Experiments with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and fluorescence with propidium iodide (PI), 4′,6-diamidino-2-phenylindole dilactate (DAPI), and green plasma revealed the cytotoxicity of 2 against these cells. Furthermore, morphological and chromogenic studies demonstrated the action of 2 on cell morphology and its inhibitory capacity of reproductive viability for colony formation in A549 cells. Furthermore, 3D experiments validated the damage caused by this diterpene in these cells. These results contribute to the search for novel compounds with antitumor potential and serve as a basis for advancing studies into the mechanisms of action of these compounds and the development of synthetic derivatives or analogs with a better antitumor profile. Full article

Pancreatic cancer often goes unnoticed in its early stages because it causes few or no symptoms, leading to late diagnoses and limited treatment options. The main challenges are delayed detection, drug resistance, and the tumor’s complexity, though progress is being made in targeted therapies, immunotherapy, metabolism-based strategies, and early detection methods. Current treatments aim to boost immune responses, extend survival, and improve quality of life. In pancreatic cancer patients, peripheral blood-derived natural killer (NK) cells show reduced numbers, decreased cytotoxic activity, and lower cytokine secretion, which may contribute to tumor growth and spread. NK cell-based immunotherapies have gained attention, with in vitro and mouse studies showing that NK cells can slow the growth of pancreatic tumor stem-like cells and encourage tumor differentiation through cytokines. Preclinical research in humanized mice suggests that NK cell therapies could reduce tumor load and restore immune function. Probiotics are also being studied in preclinical models as a potential adjuvant in therapy to restore immunity, slow tumor growth, and improve outcomes. This review compiles preclinical evidence on the benefits of combining probiotics with NK cell-based treatments for pancreatic cancer. In vitro studies indicate that probiotics can activate immune cells like peripheral blood mononuclear cells (PBMCs), NK cells, T cells, and antigen-presenting cells to help fight tumors. In humanized mouse models, combining probiotics with NK cell therapy has shown promise in reducing tumor burden, restoring immune function, and even reversing tumor-induced bone damage. The exact probiotic formulations and mechanisms are still under study, and clinical trials are in early stages without conclusive results yet. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) exhibits marked resistance to immunotherapy. Beyond its characteristically low tumor mutational burden, post-translational modifications (PTMs) remodel the immunopeptidome and promote immune escape through reversible, enzyme-driven programs. Subject Matter: We synthesize evidence that aberrant glycosylation, O-GlcNAcylation, phosphorylation, and citrullination constitute core determinants of antigen visibility operating within spatially discrete tumor niches and a desmoplastic stroma. In hypoxic regions, HIF-linked hexosamine metabolism and OGT activity stabilize immune checkpoints and attenuate antigen processing; at tumor margins, sialylated mucins engage inhibitory Siglec receptors on innate and adaptive lymphocytes; within the stroma, PAD4-dependent NET formation enforces T cell exclusion. We also delineate technical barriers to discovering PTM antigens labile chemistry, low stoichiometry, and method-embedded biases and outline practical solutions: ETD/EThcD/AI-ETD fragmentation, PTM-aware database searching and machine-learning models, and autologous validation in patient-derived organoid–T cell co-cultures. Finally, we highlight therapeutic strategies that either immunize against PTM neoepitopes or inhibit PTM machinery (e.g., PAD4, OGT, ST6GAL1), with stromal remodeling as an enabling adjunct. Conclusions: PTM biology, spatial omics, and patient sample models can uncover targetable niches and speed up PDAC vaccination, TCR, and enzyme-directed treatment development. Full article