Search Results (1,043)

Multidrug resistance (MDR) remains a major obstacle in cancer therapy, driving treatment failure and disease progression across diverse malignancies. A key determinant of MDR is the overexpression of ATP-binding cassette (ABC) transporters, particularly P-glycoprotein (P-gp/ABCB1), which actively effluxes structurally diverse chemotherapeutic agents and reduces their intracellular accumulation. Despite extensive investigation, clinically effective strategies to overcome P-gp-mediated resistance remain limited. This review provides a comprehensive analysis of the molecular mechanisms underlying P-gp function, including its structural organization, regulation of expression, and role in cellular drug disposition. We highlight the interplay between P-gp activity, oxidative stress, metabolic reprogramming and the tumor microenvironment, emphasizing the complexity of MDR as a dynamic and adaptive process. Emerging therapeutic approaches targeting P-gp-mediated resistance are also discussed, including natural bioactive compounds, nanotechnology-based drug delivery systems, polymeric carriers and novel anticancer agents designed to evade efflux mechanisms. Integrating mechanistic insights with advanced pharmacological strategies may improve intracellular drug retention and therapeutic efficacy. A deeper understanding of P-gp-driven MDR is essential for the development of effective interventions aimed at overcoming drug resistance and improving clinical outcomes in cancer patients. Full article

Prostate cancer remains a major therapeutic challenge, particularly after progression to castration-resistant disease, where persistent androgen receptor signaling, metabolic adaptation, immune escape, and treatment resistance jointly limit clinical benefit. Regulated cell death (RCD) is increasingly recognized not only as an endpoint of tumor cell elimination but also as a dynamic regulator of prostate cancer progression, therapeutic vulnerability, and tumor–immune interactions. In this review, we propose an immunometabolic framework in which androgen receptor signaling, lipid and redox metabolic reprogramming, oxidative stress, and therapeutic pressure converge to shape the susceptibility of prostate cancer cells to distinct RCD modalities. We focus on autophagy and ferroptosis as two extensively studied and translationally relevant pathways, while also discussing emerging roles of necroptosis, pyroptosis, and cuproptosis. Particular attention is given to how RCD-associated signals, including damage-associated molecular patterns, inflammatory mediators, and lipid peroxidation products, may remodel the tumor immune microenvironment and influence the transition between immune-cold and immune-inflamed phenotypes. We further summarize RCD-targeted therapeutic strategies, including ferroptosis induction, autophagy inhibition, nanodrug delivery systems, rational combination therapy, and biomarker-guided patient stratification. Finally, we discuss key translational barriers, including context-dependent biological effects, limited clinical validation, tumor heterogeneity, adaptive resistance, and insufficient predictive biomarkers. By integrating cell death biology with metabolic reprogramming, immune remodeling, and therapeutic resistance, this review highlights RCD as a promising but context-dependent therapeutic vulnerability in advanced prostate cancer. Full article

Aberrant RNA splicing and metabolic reprogramming are defining hallmarks of cancer that were historically studied as parallel processes. Increasing evidence now reveals extensive crosstalk between these pathways, whereby RNA splicing reshapes metabolic circuits, and metabolic states reciprocally influence splice-site selection and spliceosome activity. In this review, we synthesize recent mechanistic insights into how splicing programs regulate metabolic adaptation across diverse cancer contexts. We discuss recurrent oncogenic mutations in spliceosomal components and dysregulation of RNA-binding proteins (RBPs) that drive alternative splicing events in key metabolic regulators, which promote metabolic plasticity required for tumor growth. We further examine how metabolites and nutrient-sensing pathways directly modulate splicing factor activity, spliceosome dynamics, and RNA processing. We also summarize a new mechanism of mitochondrial quality control mediated by retrograde signals from mitochondria to the spliceosome to enhance mitophagy of dysfunctional mitochondria. Full article

Cancer stem cells (CSCs) constitute a resilient tumor subpopulation responsible for multidrug resistance, metastasis, and clinical relapse. A cardinal hallmark of these cells is profound metabolic plasticity. This dynamic defense mechanism facilitates rapid shifts between glycolysis, oxidative phosphorylation (OXPHOS), and alternative nutrient catabolism, enabling CSCs to bypass microenvironmental constraints. This review delineates how glycolytic adaptation functions as a primary driver of therapy resistance within the CSC niche. We dissect the regulatory triad controlling these metabolic shifts, which includes rate-limiting enzymes, epigenetic and epitranscriptomic remodeling, and master transcription factors. Glycolytic reprogramming transcends bioenergetics by acting as a metabolic signaling node. It integrates with the epithelial–mesenchymal transition (EMT) program, autophagic pathways, and the immunosuppressive tumor microenvironment (TME) to fortify CSC survival. We appraise emerging therapeutic interventions targeting these metabolic vulnerabilities. Strategies focus on optimizing small-molecule inhibitors, nanotechnology-enabled delivery systems, and immunometabolic combination regimens. This review establishes a conceptual framework for precision interventions aimed at disrupting CSC plasticity, overcoming therapeutic resistance, and preventing tumor recurrence. Full article

Cancer remains one of the most formidable health challenges worldwide. Extensive research has shown that tumor progression is not driven solely by malignant cells but is profoundly shaped by the tumor microenvironment (TME), which influences cancer initiation, immune evasion, and metastatic spread. Consequently, the TME has become an increasingly compelling therapeutic target. Nanotechnology has transformed cancer diagnostics and therapy, with metallic nanoparticles (mNPs) gaining particular attention due to their distinctive physicochemical properties and broad therapeutic potential. However, their interactions within the TME remain insufficiently understood, particularly with the non-cancerous cellular components, such as Cancer-Associated Fibroblasts (CAFs), Tumor-Associated Macrophages (TAMs), Dendritic Cells (DCs), Natural Killer (NK) cells, and T cells. Most existing reviews emphasize nanoparticle interactions with non-cellular TME components, such as the extracellular matrix, while far less attention has been given to their effects on cellular constituents (a gap this work specifically addresses). Although several molecular pathways through which mNPs modulate TME-resident cells have been identified, these likely represent only a small portion of the underlying mechanisms explored in this review. Progress in the field is further hindered by the limited availability of physiologically relevant experimental models; current in vitro and in vivo systems often fail to capture the complexity and dynamic heterogeneity of the TME. These limitations highlight the urgent need for more comprehensive and mechanistically grounded studies to validate the TME as a viable therapeutic target for nanoparticle-based cancer interventions. In particular, deeper insights into how mNPs influence immune regulation, stromal remodeling, and metabolic reprogramming within the TME will be essential for unlocking their full therapeutic potential in oncology. Full article

Anaplastic thyroid carcinoma (ATC) represents the most aggressive thyroid malignancy, characterized by rapid progression, therapeutic resistance, and poor prognosis. Conventional treatments remain largely ineffective, highlighting the need for novel therapies. Metabolic reprogramming, particularly the Warburg effect (WE), has emerged as a promising area of investigation. This review synthesizes current evidence on the role of WE in ATC and PDTC, integrating data from molecular profiling, preclinical studies, and emerging therapeutic strategies. Oncogenic alterations frequently observed in ATC, including mutations in BRAF, RAS, TP53, and activation of PI3K/AKT/mTOR and HIF-1α signaling, converge to promote glycolytic reprogramming. This metabolic shift supports tumor proliferation, immune evasion, and metastasis through increased glucose uptake, lactate production, and microenvironmental remodeling. Key metabolic nodes, including glucose transporters, hexokinase, and monocarboxylate transporters, are regarded as promising targets. Preclinical studies suggest that pharmacological inhibition of these pathways reduces tumor growth, enhances radiosensitivity, and improves response to targeted therapies. Future efforts should focus on combination therapies, biomarker-driven patient stratification, and the development of targeted delivery systems to overcome toxicity and resistance. A deeper understanding of tumor metabolic heterogeneity will be essential for translating these approaches into clinical practice. Full article

Hepatocellular carcinoma (HCC) is sustained by coordinated interactions among malignant hepatocytes, immune cells, and stromal populations that collectively drive tumor growth, immune evasion, and vascular remodeling. Using integrative single-cell transcriptomics on 93,032 cells from tumor and healthy human liver, we characterized cell-type-specific transcriptional programs underlying immunometabolic reprogramming and reconstructed the intercellular communication circuits that maintain the tumor microenvironment. Malignant hepatocytes displayed upregulation of genes encoding both glycolytic and oxidative phosphorylation (OXPHOS) metabolic enzymes, consistent with metabolic plasticity, while concurrently suppressing genes involved in antigen presentation—a transcriptional pattern indicative of coordinated metabolic and immune-evasive reprogramming. Tumor-associated macrophages acquired TREM2-enriched, lipid-handling phenotypes consistent with immunosuppressive polarization, and tumor endothelial cells upregulated angiocrine and extracellular matrix programs while silencing innate immune outputs. Ligand–receptor inference revealed a qualitative rewiring of intercellular communication: the antigen-presentation-centered network of the healthy liver was replaced by a tumor-driven architecture dominated by pro-angiogenic, ECM–integrin, inflammatory chemokine, and lipid-associated signaling circuits, with malignant hepatocytes, TAMs, and TECs collectively assuming the dominant signaling burden. These findings establish that HCC progression is an emergent property of a stabilized multicellular network, rather than the autonomous behavior of malignant cells, and define cooperative immunometabolic modules that constitute tractable targets for combinatorial therapeutic intervention. Full article

Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality, with substantial heterogeneity that is not fully explained by genetic alterations alone. Emerging evidence positions metabolic reprogramming as a central driver of tumor behavior, integrating glycolysis, mitochondrial function, lipid and amino acid metabolism, and autophagy into coordinated networks that extend beyond cancer cells to the tumor microenvironment. Tumor–immune metabolic competition and metabolite-mediated signaling shape immune responses, often promoting immunosuppression and resistance to immunotherapy, particularly in microsatellite-stable (MSS) CRC. Systemic factors, including obesity, insulin resistance, and the diet–microbiota axis, further modulate tumor metabolism and immune function, reinforcing disease progression. Metabolic biomarkers reflecting these multi-level interactions, spanning tumor-intrinsic pathways, immune contexture, and host metabolism, offer promising opportunities for improved patient stratification and therapeutic targeting, although clinical validation remains limited. Current treatments, including chemotherapy, targeted agents, and immune checkpoint inhibitors, are effective in selected subgroups but are constrained by resistance mechanisms. In this review, we propose an integrative immunometabolic framework in which tumor, immune, and systemic metabolic processes co-evolve, defining CRC progression and treatment response. Targeting this interconnected network through combinatorial and metabolism-oriented strategies may enable precision therapies, particularly for immunotherapy-resistant MSS CRC. Full article

Macrophages are highly plastic innate immune cells that adopt context-dependent phenotypes along a continuum, integrating developmental origin with local microenvironmental cues rather than conforming to discrete M1/M2 states. This review delineates the molecular circuits shaping macrophage identity—TLR/cytokine signaling, microRNA networks, metabolic rewiring, and epigenetic mechanisms including histone lactylation—and traces how circulating monocyte subsets contribute to tissue macrophage diversity. We examine macrophage plasticity across a broad disease spectrum—oncology, autoimmune and rheumatic diseases, inflammatory bowel disease, infectious diseases, metabolic disorders, and neurological conditions—showing that the pathogenic phenotype is strikingly context-dependent: for instance, M2-like tumor-associated macrophages promote immune evasion in solid tumors, whereas M1-skewed programs drive tissue damage in autoimmunity. Soluble markers (sCD163, sCD14, soluble mannose receptor) are emerging biomarkers of disease activity and prognosis. High-dimensional flow cytometry and mass cytometry (CyTOF) bridge molecular biology and clinical phenotyping, enabling integrated readouts of surface phenotype, intracellular signaling, and metabolic state. Therapeutic strategies discussed include selective tumor-associated macrophage (TAM) reprogramming, chimeric antigen receptor (CAR)-M cell therapies, and biomaterial-based platforms. Future priorities encompass spatially resolved multi-omics, epigenetic and metabolic targeting, and macrophage-centered vaccine approaches. Standardized cytometry panels will be essential for biomarker-guided stratification and context-specific interventions. Full article

Neuroblastoma (NB), the most common extracranial solid tumor of childhood, exemplifies one of the most formidable paradigms of tumor immune evasion (TIME) in pediatric oncology. Despite significant advances in multimodal therapy and the clinical integration of immunotherapeutic strategies, high-risk NB (HR-NB) remains largely refractory to durable immune control. This failure reflects not an absence of immune engagement, but the presence of a highly evolved and developmentally wired immune escape architecture. In this review, we synthesize emerging insights from single-cell, multi-omics, and functional studies to define how developmental lineage, cellular plasticity, metabolic rewiring, epigenetic regulation, and therapy-induced adaptation converge to engineer immune blindness in NB. We discuss how NB’s neural crest origin establishes a baseline of low immunogenicity, which is subsequently reinforced through coordinated suppression of antigen presentation, dominance of immune checkpoint signaling, and profound dysfunction of cytotoxic T and natural killer cells within an immunosuppressive tumor microenvironment. Central to this process is tumor-intrinsic plasticity, whereby lineage instability and dedifferentiation, exacerbated by therapeutic pressure, embed immune silence as a stable tumor state. We highlight evidence positioning RD3 as a master upstream regulator linking cellular identity to immune visibility, governing antigen presentation, innate immune sensing, checkpoint expression, and cytotoxic lymphocyte engagement. Beyond tumor-intrinsic mechanisms, we examine the roles of immunosuppressive myeloid populations, tumor-derived exosomes, metabolic stress, hypoxia, and ferroptosis-associated pathways in reinforcing immune paralysis. Finally, we outline emerging therapeutic strategies aimed at dismantling this architecture, including combinatorial checkpoint blockade, metabolic and epigenetic reprogramming, exosome-targeted interventions, and next-generation immune engineering platforms. Together, this review reframes TIME in NB as a programmable, developmentally rooted process and provides a mechanistic roadmap for restoring immune competence and therapeutic susceptibility in HR disease. Full article

Background/Objectives: Whether anesthetic maintenance influences tumor biology in cervical cancer remains unsettled. We examined whether plasma extracellular vesicles (EVs) collected during sevoflurane or propofol anesthesia differentially affect HeLa cell behavior and explored lipidomic alterations associated with the biologically active EV condition. Methods: In a single-center prospective observational cohort, paired plasma samples were collected before anesthesia induction and before wound closure from 53 patients with stage II cervical cancer undergoing radical surgery under sevoflurane (n = 28) or propofol (n = 25) anesthesia. EV preparations were characterized by transmission electron microscopy, nanoparticle tracking analysis, and immunoblotting for EV markers. Their effects on HeLa cell proliferation, invasion, and wound closure, as well as HUVEC tube formation, were examined in vitro. EV miRNA profiles were analyzed by small-RNA sequencing. Lipidomic profiling by LC-MS and immunoblot analysis of EGFR/PKCα/NF-κB signaling were performed in recipient HeLa cells exposed to sevoflurane-associated EVs. Results: EVs collected after sevoflurane anesthesia increased HeLa cell proliferation, invasion, and wound closure and enhanced endothelial branching in HUVEC tube-formation assays, whereas post-propofol EVs showed no comparable phenotype. Small-RNA sequencing identified distinct anesthesia-associated EV miRNA changes, with the sevoflurane-related signature enriched in glycerolipid metabolism, glycerophospholipid metabolism, glycosylphosphatidylinositol-anchor biosynthesis, phosphatidylinositol signaling, and inositol phosphate metabolism. In HeLa cells treated with post-sevoflurane EVs, lipidomic analysis showed clear separation from pre-sevoflurane EV-treated cells and identified increased diacylglycerol (DG) species, including DG (16:1/18:2), DG (16:0/16:1), DG (18:2/18:2), DG (18:2/20:4), and DG (16:0/18:2). These changes were accompanied by higher p-EGFR, PKCα, and p-NF-κB p65 levels. Several DG species correlated positively with proliferation and invasion readouts and inversely with residual wound area. Conclusions: Plasma EVs collected after sevoflurane anesthesia were associated with a more aggressive phenotype in recipient cervical cancer cells and with lipid remodeling characterized by DG accumulation and altered EGFR/PKCα/NF-κB signaling. The data support an exploratory mechanistic model linking sevoflurane-associated EV cargo to metabolic reprogramming in cervical cancer cells. Full article

Colorectal cancer (CRC) is a major global health burden characterized by progressive genetic and metabolic alterations, with iron metabolism being increasingly recognized as a key contributor to tumorigenesis. This review provides an integrated synthesis of current evidence on iron metabolism across the continuum of colorectal cancer development, from preneoplastic lesions to advanced disease. We analyzed data from epidemiological, experimental, and mechanistic studies addressing systemic and cellular iron homeostasis, including the hepcidin–ferroportin axis, as well as iron handling within tumor cells and the tumor microenvironment. Available data indicate that colorectal epithelial cells progressively develop an iron-retentive phenotype, characterized by increased iron uptake and reduced export, leading to expansion of the intracellular labile iron pool. This imbalance contributes to oxidative stress, DNA damage, metabolic adaptation, and activation of oncogenic signaling pathways while also influencing immune responses. However, epidemiological findings on dietary iron and CRC risk remain inconsistent, highlighting the context-dependent nature of iron-related effects. In conclusion, iron metabolism represents a dynamic regulator of CRC progression and a mechanistic framework for understanding stage-specific tumor evolution, although further studies are needed to clarify how iron-dependent pathways differ across colorectal tumor subtypes and microenvironmental contexts. Full article

Tumor metastasis constitutes a frequent contributor to high mortality rates, with EMT intimately implicated in this disseminative process. Accumulating evidence in recent years indicates that neoplastic cells undergoing EMT frequently exhibit concurrent metabolic reprogramming. Multiple modalities—including glycolysis, mitochondrial oxidative phosphorylation, lipid metabolism, as well as amino acid metabolism—cooperatively supply energy, facilitate membrane remodeling, and sustain redox homeostasis. Specifically, glycolytic flux, oxidative phosphorylation, lipid turnover, and amino acid catabolism/anabolism function in a concerted manner to meet the bioenergetic demands, support biogenesis of cellular membranes, and preserve the intracellular redox equilibrium during phenotypic conversion. Notably, intermediate metabolites can in turn modulate the trajectory of EMT through signal transduction cascades or epigenetic modifications. This review systematically delineates the bidirectional regulatory circuitry interconnecting EMT and metabolic reprogramming; furthermore, it examines the implications of this crosstalk for neoplastic disease progression. Finally, therapeutic strategies targeting the nexus of metabolic reprogramming and EMT are summarized. Full article

Normal prostate epithelial cells accumulate high intracellular zinc levels that maintain optimum mitochondrial metabolism and proliferation. Prostate cancer cells lose this zinc-accumulating capacity, enabling metabolic reprogramming that supports tumor progression. Restoring intracellular zinc selectively in prostate tumors represents a promising therapeutic strategy; however, systemic zinc administration is limited by the inability of prostate cancer cells to take up free zinc resulting from ZIP1 transporter downregulation. To overcome this challenge, we developed a formulation of prostate-specific membrane antigen (PSMA)-targeted, zinc-loaded liposomes (Zn-TL) to enable tumor-selective intracellular zinc delivery. Zn-TL was prepared with uniform nanoscale size, low polydispersity, and negative surface charge. The formulation showed minimal zinc leakage during storage and sustained retention in vitro. In prostate cancer cells, Zn-TL demonstrated receptor-mediated uptake, resulting in increased cytotoxicity and apoptosis. In vivo, we performed proof-of-principle studies showing prolonged circulation and tumor accumulation of Zn-TL in mice bearing PSMA-positive tumors. While tumor growth was delayed during early and intermediate stages of tumor development, this effect diminished at later stages. The stage-dependent efficacy suggests that Zn-TL may be most effective when used earlier in disease progression. These results also suggest that Zn-TL represents a promising platform for metabolic intervention and may benefit from combination strategies to enhance efficacy in advanced disease. Full article

Mitochondrial dysfunction is not merely a byproduct of transformation but a driver of tumorigenesis, metastasis, and therapeutic resistance. Recent advancements in intercellular communication have identified Extracellular Vesicles (EVs) or exosomes as critical mediators that bridge the gap between the tumor and its microenvironment (TME). These EVs contain a complex repertoire of bioactive cargo, including proteins, lipids, and RNAs. Among the class of RNAs, small non-coding RNAs, microRNAs (miRNAs), are the most abundantly expressed bioactive compounds that are selectively packaged and delivered to recipient cells. EV-delivered miRNAs can target nuclear-encoded mitochondrial genes and have also been reported to localize to mitochondria (mitomiRs), where they function as post-transcriptional regulators of bioenergetic and mitochondrial dynamic adaptations that support tumor progression. This review explores the “EV-miRNA-Mitochondria Axis”, delineating the molecular mechanisms by which EV-carried miRNAs reprogram the “Mitochondrial Information Processing System” (MIPS) - a signaling network where mitochondria integrate metabolic cues (e.g., ROS, calcium flux) to dictate critical biological outcomes, such as immune regulation and cell survival. We summarized specific sorting machineries (e.g., hnRNPA2B1, Lupus La) that package oncogenic miRNAs into EVs and how these cargoes hijack mitochondrial function upon delivery. Specifically, we discussed how EV-miRNAs induce metabolic shifts, manipulate mitochondrial dynamics (fission/fusion), and inhibit the intrinsic apoptosis to drive cancer progression. Finally, we highlighted the dual utility of these EV-miRNAs as drivers of pathogenesis and promising non-invasive biomarkers for early diagnosis, prognostic and therapeutic monitoring. Full article